Compounds with analgesic effect

ABSTRACT

Compounds of general formula (I)                    
     are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 09/029,633,filed on Mar. 5, 1998, U.S. Pat. No. 6,187,792 and claims the benefitthereof. The ‘633 application represents U.S. national stage ofinternational application PCT/SE97/02050, with an international filingdate of Dec. 9, 1997. The international application claims priority toSwedish application nos. 9604785-7, filed Dec. 20, 1996, and 9702535-7,filed Jul. 1, 1997.

FIELD OF THE INVENTION

The present invention is related to novel compounds, to a process fortheir preparation, their use and pharmaceutical compositions comprisingthe novel compounds. The novel compounds are useful in therapy, and inparticular for the treatment of pain.

BACKGROUND AND PRIOR ART

The δ receptor has been identified as having a role in many bodilyfunctions such as circulatory and pain systems. Ligands for the δreceptor may therefore find potential use as analgesics, and/or asantihypertensive agents. Ligands for the δ receptor have also been shownto possess immunomodulatory activities.

The identification of at least three different populations of opioidreceptors (μ, δ and κ) is now well established and all three areapparent in both central and peripheral nervous systems of many speciesincluding man. Analgesia has been observed in various animal models whenone or more of these receptors has been activated.

With few exceptions, currently available selective opioid δ ligands arepeptidic in nature and are unsuitable for administration by systemicroutes. Some non-peptidic δ antagonists have been available for sometime (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32:239-269. for review). These compounds, e.g. naltrindole, suffer fromrather poor (i.e., <10-fold) selectivity for the δ receptor vs. μreceptor binding and exhibit no analgesic activity, a fact whichunderscores the need for the development of highly selectivenon-peptidic δ ligands.

Thus, the problem underlying the present invention was to find newcompounds having improved analgesic effects, but also with an improvedside-effect profile over current μ agonists and potential oral efficacy.

Analgesics that have been identified and are existing in the prior arthave many disadvantages such as that they suffer from poorpharmacokinetics and are not analgesic when administered by systemicroutes. Also, it has been documented that preferred compounds, describedwithin the prior art, show significant convulsive effects whenadministered systemically.

The problem mentioned above has been solved by developing novelcompounds which possess a piperidine ring with an exocyclic double bond,as will be described below.

OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined bythe general formula (I)

wherein

R¹ is selected from hydrogen, a branched or straight C₁-C₆ alkyl, C₁-C₆alkenyl, C₃-C₈ cycloalkyl, C₄-C₈(alkyl-cycloalkyl) wherein alkyl isC₁-C₂ alkyl and cycloalkyl is C₃-C₆ cycloalkyl;

C₆-C₁₀ aryl; or heteroaryl having from 5 to 10 atoms selected from anyof C, S, N and O; wherein the aryl and heteroaryl may optionally andindependently be substituted by 1 or 2 substituents independentlyselected from any of hydrogen, CH₃, —(CH₂)_(p)CF₃, halogen, —CONR⁵R⁴,—COOR⁵, —COR⁵, —(CH₂)_(p)NR⁵R⁴, —(CH₂)_(p)CH₃(CH₂)_(p)SOR⁵R⁴,—(CH₂)_(p)SO₂R₅, and —(CH₂)_(p)SO₂NR⁵, wherein R⁴ and R⁵ is each andindependently as defined for R¹ above and p is 0, 1 or 2;

(C₁-C₂ alkyl)-(C₆-C₁₀ aryl); or (C₁-C₂ alkyl)heteroaryl, the heteroarylmoieties having from 5 to 10 atoms selected from any of C, S, N and O,and where the aryl or heteroaryl may optionally and independently besubstituted by 1 or 2 substituents independently selected from any ofhydrogen, CH₃, —(CH₂)_(q)CF₃, halogen, —CONR⁵R⁴, —COOR⁵, —COR⁵,—(CH₂)_(q)NR⁵R⁴, —(CH₂)_(q)CH₃(CH₂)_(q)SOR⁵R⁴, —(CH₂)_(q)SO₂R⁵,—(CH₂)_(q)SO₂NR⁵ and —(CH₂)_(p)OR⁵, wherein R⁴ and R⁵ is each andindependently as defined for R¹ above and q is 0, 1 or 2; and

wherein R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ is each andindependently hydrogen, C₁-C₆ alkyl or C₁-C₆ alkenyl;

R² and R³ is each and independently hydrogen or C₁-C₆ alkyl;

A is selected from

wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is each andindependently as defined for R¹ above, and wherein the phenyl ring ofeach A substituent may be optionally and independently substituted atany position of the phenyl ring by 1 or 2 substituents Z¹ and Z² whichare each and independently selected from hydrogen, CH₃, —(CH₂)_(q)CF₃,halogen, —CONR⁶R⁷, —COOR6, —COR⁶, —(CH₂)_(r)NR⁶R⁷,—CH₂)_(r)CH₃(CH₂)_(r)SOR⁶, —(CH₂)_(r)SO₂R⁶ and —(CH₂)_(r)SO₂NR⁶R⁷wherein R⁶ and R⁷ is each and independently as defined for R¹ above andr is 0, 1, or 2;

Q is C₅-C₆ hydroaryl or heterohydroaromatic having 5 or 6 atoms selectedfrom anyone of C, S, N and O; C₅ -C₆ cykloalkyl, or heterocycloalkylhaving 5 or 6 atoms selected from anyone of C, N, O and S; and whereeach Q may optionally be substituted by a substituent Z¹ and Z² asdefined above;

B is a substituted or unsubstituted aromatic, heteroaromatic,hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atomsselected from any of C, S, N and O, optionally and independentlysubstituted by 1 or 2 substituents independently selected from hydrogen,CH₃, —(CH₂)_(t)CF₃, halogen, —(CH₂)_(t)CONR⁵R⁴, —(CH₂)_(t)NR⁵R⁴,—(CH₂)_(t)COR⁵, —(CH₂)_(t)COOR⁵, —OR⁵, —(CH₂)_(t)SOR⁵, —(CH₂)_(t)SO₂R⁵,and —(CH₂)tSO₂NR⁵R⁴, wherein R⁴ and R⁵ is each and independently asdefined for R¹ above, and t is 0, 1, 2 or 3; and

R⁴ and R⁵ is each and independently as defined for R¹ above.

Within the scope of the invention are also pharmaceutically acceptablesalts of the compounds of the formula (I), as well as isomers, hydrates,isoforms and prodrugs thereof.

Preferred compounds according to the invention are compounds of theformula (I) wherein

A is selected from

wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is each andindependently as defined for R¹ above, and wherein the phenyl ring ofeach A substituent may be optionally and independently substituted atany position of the phenyl ring by 1 or 2 substituents Z¹ and Z² whichare each and independently selected from hydrogen, CH₃, —(CH₂)_(q)CF₃,halogen, —CONR⁶R⁷, —COOR⁶, —COR⁶, —(CH₂)_(r)NR⁶R⁷,—(CH₂)_(r)CH₃(CH₂)_(r)SOR⁶, —(CH₂)_(r)SO₂R⁶ and —(CH₂)_(r)SO₂NR⁶R⁷wherein R⁶ and R⁷ is each and independently as defined for R¹ above, andr is 0, 1, or 2;

Q is selected from morpholine, piperidine and pyrrolidine;

R¹, R⁴, and R⁵ is each and independently selected from hydrogen, abranched or straight C₁-C₄ alkyl, C₃-C₅ cycloalkyl, C₄-C₈(alkyl-cycloalkyl) wherein alkyl is C₁-C₂ alkyl and cycloalkyl is C₃-C₆cycloalkyl; C₆-C₁₀ aryl; and heteroaryl having from 5 to 6 atomsselected from any of C, S, N and O; and where the aryl or heteroaryl mayoptionally and independently be substituted by 1 or 2 substituentsindependently selected from any of hydrogen, CH₃, —(CH₂)_(p)CF₃,halogen, —CONR⁵R⁴, —COOR⁵, —COR⁵, —(CH₂)_(p)NR⁵R⁴,—(CH₂)_(p)CH₃(CH₂)_(p)SOR⁵R⁴, —(CH₂)_(p)SO₂R⁵, and —(CH₂)_(p)SO₂NR⁵,wherein R⁴ and R⁵ is each and independently as defined for R¹ above andp is 0, 1 or 2;

B is selected from phenyl, naphthyl, indolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl,isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl,indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl,tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, andindazolinyl, each optionally and independently substituted by 1 or 2substituents independently selected from hydrogen, CH₃, CF₃, halogen,—(CH₂)_(q)CONR⁵R⁴, —(CH₂)_(q)NR⁵R⁴, —(CH₂)_(q)COR⁵, —(CH₂)_(q)CO₂R⁵, and—OR⁵, wherein q is 0 or 1, and wherein R⁴ and R⁵ are as defined above;

R² and R³ is each and independently hydrogen or methyl.

Especially preferred compounds according to the invention are compoundsof the formula (I) wherein

A is

wherein R⁸ and R⁹ are both ethyl, and where the phenyl ring optionallyand independently may be substituted at any position of the phenyl ringby 1 or 2 substituents Z¹ and Z² which are each and independentlyselected from hydrogen, CH₃, —(CH₂)_(q)CF₃, halogen, —(CONR⁶R⁷, —COOR⁶,—COR⁶, —(CH₂)_(r)NR⁶R⁷, —(CH₂)_(r)CH₃(CH₂)_(r)SOR⁶, —(CH₂)_(r)SO₂R⁶ and—(CH₂)_(r)SO₂NR⁶R⁷ wherein R⁶ and R⁷ is each and independently asdefined for R¹ above and r is 0, 1, or 2;

R¹ is selected from hydrogen, methyl, ethyl, —CH₂CH═CH₂,—CH₂-cyclopropyl, —CH₂-aryl, or CH₂-heteroaryl, the heteroaryl moietieshaving from 5 to 6 atoms selected from any of C, S, N and O;

B is selected from phenyl, naphthyl, indolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl,isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl,indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl,tetrahydroisoquinolinyl, tetrahydrofuranyl, and indazolinyl, eachoptionally and independently substituted by 1 or 2 substituentsindependently selected from hydrogen, CH₃, CF₃, halogen,—(CH₂)_(q)CONR⁵R⁴, —(CH₂)_(q)NR⁵R⁴, —(CH₂)_(q)COR⁵, —(CH₂)_(q)CO₂R⁵, and—OR⁵, wherein q is 0 or 1, and wherein R⁴ and R⁵ are as defined above;

R² and R³ is each and independently hydrogen or methyl.

The substituents A and B respectively, may optionally be substituted atany position of the ring.

By “halogen” we mean chloro, fluoro, bromo and iodo.

By “aryl” we mean an aromatic ring having from 6 to 10 carbon atoms,such as phenyl and naphtyl.

By “heteroaryl” we mean an aromatic ring in which one or more of thefrom 5-10 atoms in the ring are elements other than carbon, such as N, Sand O.

By “hydroaromatic” we mean a partly or fully saturated aromatic ringstructure having 5-10 carbon atoms in the ring.

By “heterohydroaromatic” we mean a partly or fully saturated aromaticring structure in which one or more of the 5-10 atoms in the ring areelements other than carbon, such as N, S and O.

By “isomers” we mean compounds of the formula (I), which differ by theposition of their functional group and/or orientation. By “orientation”we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.

By “isoforms” we mean compounds of the formula (I) which differ by theircrystal lattice, such as crystalline compound and amorphous compounds.

By “prodrug” we mean pharmacologically acceptable derivatives, e.g.esters and amides, such that the resulting biotransformation product ofthe derivative is the active drug. The reference by Goodman and Gilmans,The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int.Ed. 1992, “Biotransformation of Drugs, p. 13-15, describing prodrugsgenerally, is hereby incorporated.

The novel compounds of the present invention are useful in therapy,especially for the treatment of various pain conditions such as chronicpain, acute pain, cancer pain, pain caused by rheumatoid arthritis,migraine, visceral pain etc. This list should however not be interpretedas exhaustive.

Compounds of the invention are useful as inmmunomodulators, especiallyfor autoimmune diseases, such as arthritis, for skin grafts, organtransplants and similar surgical needs, for collagen diseases, variousallergies, for use as anti-tumour agents and anti viral agents.

Compounds of the invention are useful in disease states wheredegeneration or dysfunction of opioid receptors is present or implicatedin that paradigm. This may involve the use of isotopically labelledversions of the compounds of the invention in diagnostic techniques andimaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea,depression, urinary incontinence, various mental illnesses, cough, lungoedema, various gastro-intestinal disorders, spinal injury and drugaddiction, including the treatment of alcohol, nicotine, opioid andother drug abuse and for disorders of the sympathetic nervous system forexample hypertension.

Compounds of the invention are useful as an analgesic agent for useduring general anaesthesia and monitored anaesthesia care. Combinationsof agents with different properties are often used to achieve a balanceof effects needed to maintain the anaesthetic state (e.g. Amnesia,analgesia, muscle relaxation and sedation). Included in this combinationare inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockersand opioids.

The compounds of the present invention in isotopically labelled form areuseful as a diagnostic agent.

Also within the scope of the invention is the use of any of thecompounds according to the formula (I) above, for the manufacture of amedicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to the formula (I) above, isadministered to a patient in need of such treatment.

Methods of Preparation

The compounds of the present invention may be prepared as described inthe following.

As shown in SCHEME I & II above, compounds of the formula (I) above, maybe obtained by dehydration of hydroxy compounds (g) or (h), wherein R¹,R², R³, A and B are as defined in formula (I) above. Subsequentdehydration of hydroxyl compounds (g) or (h), wherein R¹, R², R³, A andB are as defined in formula (I), may be performed without solvents or ina solvent such as water, alcohols, esters, HMPA, dichloromethane,toluene, ethers, ketones, carboxylic acids or in a solvent mixture inthe presence of Brønstedt or Lewis acids such as sulphuric acid,hydrochloric acid, trifluoroacetic acid, aluminium trichloride, ZnCl₂ orthe like, or in the presence of metallic oxides such as Al₂O₃, Cr₂O₃,TiO₂, WO₃, P₂O₅ or the like, or in the presence of other dehydratingagents such as I₂, dimethyl sulfoxide, KHSO₄, CuSO₄, phthalic anhydrideor the like.

The substituents R¹, R² and R³ and the substituents on A and B ofcompound (I), as defined above, may be modified by methods known in theart and exemplfied in the literature, see e.g. Protecting groups byGreen, or Modern Synthetic Reactions by House, which are well known to aperson skilled in the art, after or during the preparation of (I) from(g) and (h).

As shown the route a of SCHEME I, compounds of formula (g), as describedabove, may be obtained by a reaction between a ketone of formula (c)wherein R¹, R² and R³ are as defined in formula (I), and a compound offormula (e) wherein A and B are as defined in formula (I), and X is asuitable group such as H, Cl, Br, I, OSO₂R or the like.

The reaction may be performed without solvents, or in an organic solventsuch as THF toluene, ethers, dimethylsulfoxide, or in solvent mixturesby treatment with an appropriate metal such as magnesium, lithium, zinc,copper, cerium or the like, or by treatment with a metal halide such asSmI₂, CrCl₂ or the like, or by treatment with an organometallic agentssuch as alkylmagnesium halides, alkyllithium or the like.

R¹, R² and R³ and the substituents on A and B of compounds (g), asdefined above, may be modified, by methods known in the art, after orduring the organometallic reactions (March, J., Advanced OrganicChemistry, 4^(th) Ed, John Wiley & Sons, 1992).

Compounds of formula (c) and (e) may be commercially available, orprepared by methods known in the art (March, J., Advanced OrganicChemistry, 4^(th) Ed, John Wiley & Sons, 1992).

As shown in route b of SCHEME II, compounds of formula (h), as describedabove, may be obtained by a reaction between a ketone of formula (i)wherein R¹, R² and R³, and B are as defined in formula (I), and anorganometallic reagent of formula (j) wherein A is as defined in formula(I), and M is an appropriate metal group such as magnesium, lithium,zinc, copper, cerium or the like. The reaction may be performed withoutsolvents, or in an organic solvent such as THF, toluene, ethers,dimethylsulfoxide, or in solvent mixtures.

As shown in route c of SCHEME II, compounds of formula (h) may also beobtained by reactions among a carbonyl compound of formula (I), whereinR¹, R² and R³ are as defined in formula (I), and X is an appropriateleaving group such as Cl, Br, OH, OR, SR, NR₂, N(OR′)R or the like, andorganometallic reagents of formula (j) and (k), wherein A and B are asdefined in formula (I), and M is an appropriate metal group such asmagnesium, lithium, zinc, copper, cerium or the like. The reactions maybe performed without solvents or in solvents such as THF, toluene,ethers, dimethyl formamide, dioxane, dimethylsulfoxide, or in solventmixtures.

R¹, R² and R³ and the substituents on A and B of compounds (h), asdefined above, may be modified, by methods known in the art andexemplfied in the literature, see e.g. Protecting groups by Green, orModern Synthetic Reactions by House, which are well known to a personskilled in the art, after or during the organometallic reactions.

Compounds of formula (i), (j), (k) and (l) may be commerciallyavailable, or prepared by methods known in the art (March, J., AdvancedOrganic Chemistry, 4^(th) Ed, John Wiley & Sons, 1992).

As shown in SCHEME III above, compounds of the formula (I) above, may beobtained from the Suzuki coupling of vinylic halide (o) (X=Br, I) with aboronic acid, boronate ester (p), in the presence of a base such asNa₂CO₃, K₂CO₃, K₃PO₄, triethylamine, CsF, NaOH or alkoxides andpalladium catalyst such as (PPh₃)₄Pd, Bis(dibenzylideneacetone)Pd(0), Pdon carbon with PPh₃; Pd(II) species may also be used as a catalystincluding: (PPh₃)₂PdCl₂, 1,4-Bis(diphenylphosphinobutane)palladium(II)chloride, Palladium acetate, Bis(acetonitrile)palladium(II) chloride,dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) andpalladium acetate-tri(0-tolyl)phosphine, wherein R¹, R², R³, A and B areas defined in formula (I) above. The Suzuki coupling may be performed intoluene, xylene, anisole, DMF, THF, alcohols, ethers, water or in asolvent mixture.

Compounds or formula (p), where B is as defined in formula (I) and Z isB(OH)₂, may be commercially available or prepared from the hydrolysis ofa boronate ester. Compounds or formula (p), where B is as defined informula (I) and Z is B(OR)₂ (R=Me, Et), may be prepared from thereaction of a compound of formula B-M and B(OR)₃ where R=Me or Et, and Mis an appropriate metal group such as lithium or magnesium or the like.Compounds of formula (p) where B is as defined in formula (I) and Z is9-borabicyclo[3.3.1]nonane (9-BBN) may be prepared from the reaction ofan alk-1-yne with borabicyclo[3.3.1]nonane.

The substituents R¹, R², R³ and the substituents on A and B of compound(I) as defined above, may be modified by methods known in the art andexemplified in the literature, see e.g. Protecting groups by Green orModern Synthetic Reactions by House, which are well known to a personskilled in the art, after or during the preparation of (I) from (o) and(p).

As shown in SCHEME III, compounds of formula (o) wherein X is Br or I,may be prepared from the halogenation and elimination of an alkene offormula (n) wherein R¹, R², R³ and A are as defined in formula (I). Thehalogenation may be performed in a solvent such as dichloromethane,chloroform, carbon tetrachloride, dichloroethane, or acetic acid usingmolecular bromine or iodine as halogenation agent. The subsequentelimination step is accomplished in a solvent such as water, alcohols,DMF, or ethers using a base such as sodium hydroxide, potassiumhydroxide, metal alkoxides, or triethylamine.

As shown in SCHEME III, compounds of formula (n), as described above,may be prepared from the Wittig reaction of a ketone of formula (c),where R¹, R² and R³ are as defined in formula (I), and a reagent offormula (m) where A is as defined in formula (I) and Y is an appropriatephosphonate or phosphonium salt. The Wittig reaction may be carried outunder a variety of conditions known in the art and exemplified in theliterature (March, J., Advanced Organic Chemistry, 4^(th) Ed., JohnWiley & Sons, 1992).

Reagents of formula (c) and (m) may be commercially available, orprepared by methods known in the art (March, J., Advanced OrganicChemistry, 4^(th) Ed., John Wiley & Sons, 1992).

As shown in SCHEME IV above, compounds of formula (u) may be obtained bydehydration of hydroxy compound (t) wherein R¹, R², R³, R¹², R¹³ and Bare as defined above. Dehydration step may be performed without solventor in a solvent such as water, alcohols, esters, HMPA, dichloromethane,toluene, ethers, ketones, carboxylic acids, or in a solvent mixture inthe presence of Bronstedt or Lewis acids such as sulfuric acid,hydrochloric acid, trifluoroacetic acid, aluminium trichloride, ZnCl₂,or the like, or in the presence of metallic oxides such as Al₂O₃, Cr₂O₃,TiO₂, WO₃, P₂O₅ or the like, or in the presence of other dehydratingagents such as I₂, dimethylsulfoxide, KHSO₄, CuSo₄, phthalic anhydrideor the like.

The substituents R¹, R² and R³ and the substituent B of compound (u) asdefined above may be modified by methods known in the art andexemplified in the literature, see e.g. Protecting Groups by Green, orModern Synthetic Reactions by House, which are well known to a personskilled in the art, after or during the preparation of (u) from (t).

As shown in SCHEME IV above, compounds of formula (t) may be obtainedfrom compound (s) wherein R¹, R², R³, R¹³ and B are as defined aboveusing alkylation reaction with alkyl halide such as MeI in presence of abase such as sodium hydroxide and a phase transfer agent such asBu₄NHSO₄. Compounds of formula (s) may be prepared by a reaction betweena ketone of formula (r) wherein R¹, R², R³, R¹³ are as defined above andan organometallic reagent of formula (k) wherein B is defined in formula(I) and M is an appropriate metal group such as magnesium, lithium,zinc, copper, cerium, or the like. The reaction may be performed withoutsolvent or in solvents such as THF, toluene, ethers, dimethylformamide,dioxane, dimethylsufoxide, or in solvent mixtures.

The substituents R¹, R², R³, R¹³ of compound (s) as defined above may bemodified by methods known in the art and exemplified in the literature,see e.g. Protecting Groups by Green, or Modern Synthetic Reactions byHouse, which are well known to a person skilled in the art, after orduring the preparation of (s) from (r) and (k).

As shown in SCHEME IV, a compound of formula (r) may be obtained byreactions among a carbonyl compound of formula (l) wherein R¹, R² and R³are as defined in formula (I) and X is an appropriate leaving group suchas Cl, Br, OH, OR, SR, NR₂, N(OR′)R or the like and organometallicreagent obtained by first base treatment such as NaH on compound (q)wherein R¹³ is as defined above followed by subsequent transmetallationusing alkyl lithium such as Buli. The reaction may be performed insolvents such as THF, toluene, ethers, dimethylformamide, dioxane, or insolvent mixtures. The substituents R¹, R², R³, R¹³ of compound (r) asdefined above may be modified by methods known in the art andexemplified in the literature, see e.g. Protecting Groups by Green, orModern Synthetic Reactions by House, which are well known to a personskilled in the art, after or during the preparation of (r) from (q) and(l).

As shown in SCHEME IV, compounds of formula (q) may be obtained byacylation of 4-iodoaniline using either acylanhydride or acylchloride inan organic solvent such as dichloromethane. The substituent R¹³ ofcompound (q) is as defined above.

The invention will now be described in more detail by way of thefollowing Examples, which are not to be construed as limiting theinvention in any way.

A) Synthetic Scheme For the Preparation of the Compounds of Examples 1-7

The compounds of Examples 1-7 were prepared by following the procedureas is shown in Scheme 1 below.

(i) Preparation of N-t-ButoxylcarbonylN′-methyl-N′-methoxyl-isonipecotamide (Compound 2)

A mixture of ethyl isonipecotate (compound 1) (4.71 g, 30.0 mmol),di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) and Na₂CO₃ (4.77 g, 45mmol) in H₂O-THF (90/10 mL) was refluxed for 2 h. The reaction mixturewas extracted with ethyl acetate (150 mL). The organic layer was washedwith brine, dried over MgSO₄. Removal of solvents gaveN-t-butoxylcarbonyl ethyl isonipecotate (7.67 g):

δ_(H) (400 MHz, CDCl₃) 1.25 (t, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.62 (m,2H), 1.87 (m, 2H), 2.43 (m, 1H), 2.84 (m, 2H), 4.02 (m, 2H), 4.13 (q,J=7.2 Hz, 2H); δ_(C-13) (100 MHz, CDCl₃) δ: 14.0, 27.8, 28.2, 40.9,42.9, 60.2, 79.2, 154.4, 174.2.

The above N-t-butoxylcarbonyl ethyl isonipecotate was dissolved in dryTHF (60 mL) and mixed with NHMe(OMe) HCl (4.39 g, 45.0 mmol). Themixture was treated with i-PrMgCl (2.0 M in THF, 45 ml, 90 mmol) at −20C. and the resulting solution was stirred for 1 hr at −5° C. and thenquenched with aqueous NH₄Cl solution and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with brine, driedover MgSO₄. Removal of solvents gave N-t-butoxylcarbonylN′-methyl-N′-methoxyl-isonipecotamide (compound 2) (8.0 g, 98%):

δ_(H) (400 MHz, CDCl₃) 1.30 (s, 9H), 1.54 (m, 4H), 2.65 (m, 3H), 3.02(s, 3H), 3.56 (s, 3H), 3.99 (brs, 2H); δ_(C-13) (100 MHz, CDCl₃) δ:27.7, 28.1, 32.0, 37.8, 43.1, 61.3, 79.1, 154.4, 176.0.

(ii) Preperation of4-(4′-N′,N′-Diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine(Compound 3)

To a solution of 4-iodo-N,N-diethylbenzamide (9.09 g, 30.0 mmol) andTMEDA (6.96 g, 60.0 mmol) in dry THF (60 mL) was added t-butyllithium(35.0 mL, 1.7 M, 60.0 mmol) at −78° C. After 30 min, N-t-butoxylcarbonylN′-methyl-N′-methoxyl-isonipecotamide (compound 2) (8.0 g, 29.4 mmol) inTHF (10 mL) was dropwise added. The reaction mixture was warmed to r.t.and then quenched with aqueous NH₄Cl solution, neutralized withhydrochloric acid (concentrated, 20 mL) at ° C., and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine, dried over MgSO₄. Removal of solvents gave a crude product, whichwas purified by silica gel column eluting with MeOH-CH₂Cl₂ (2:98) toprovide4-(4′-N′,N′-diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine(compound 3) (3.15 g, 28%):

δ_(H) (400 MHz, CDCl₃) 1.08 (brs, 3H), 1.23 (brs, 3H), 1.43 (s, 9H),1.61 (m, 2H), 1.80 (m, 2H), 2.89 (m, 2H), 3.20 (brs, 2H), 3.40 (m, 1H),3.53 (brs, 2H), 4.11 (brs, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.94 (d, J=8.0Hz, 2H).

(iii) Preparation of4-(α-Hydroxyl-α-(4-N-t-butoxylcarbonylpiperidinyl)-α-(1-naphthyl)-methyl)-N,N-diethylbenzamide(Compound 4)

To a solution of 1-bromonaphthalene (0.52 g, 2.5 mmol) in dry THF (10mL) was added n-butyllithium (1.1 mL, 2.5 M, 2.75 mmol) at −78° C. After30 min,4-(4′-N′,N′-diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine(compound 3) (776 mg, 2.0 mmol) in THF (2 mL) was dropwise added. Thereaction mixture was warmed to r.t. and then quenched with aqueous NH₄Clsolution, and extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine, dried over MgSO₄. Removal ofsolvents gave a crude product, which was purified by silica gel columneluting with MeOH—CH₂Cl₂ (0.5:99.5→5:95) to provide4-(α-hydroxyl-α-(4-N-t-butoxylcarbonylpiperidinyl)-α-(1-naphthyl)-methyl)-N,N-diethylbenzanide(compound 4) (760 mg, 74%):

m.p. 121-124° C. (CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3402, 2960, 1685, 1626,1425, 1283, 1160; Anal.Calcd.for C₃₂H₄₀N₂O₄.0.50H₂O: C, 73.11; H, 7.86;N, 5.33. Found: C, 72.86; H, 7.64; N, 5.26; δ_(H) (400 MHz, CDCl₃) 1.03(brs, 3H), 1.16 (brs, 3H), 1.18-1.35 (m, 3H), 1.95 (m, 1H), 2.60 (m,2H), 2.75 (brs, 2H), 3.15 (brs, 2H), 3.42 (brs, 2H), 4.10 (brs, 2H),7.10-7.50 (m, 7H), 7.75 (m, 3H), 8.27 (brs, 1H); δ_(C-13) (100 MHz,CDCl₃) δ: 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4, 79.3, 80.4,124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128.8, 129.2, 131.4, 135.0,135.2, 139.4, 146.5, 154.6, 171.0.

(iv) Preparation of4-(α-Hydroxyl-α-(4-N-t-butoxylcarbonylpiperidinyl)-2,6-dimethylbenzyl)-N,N-diethylbenzamide(Compound 5)

Method as described for compund 4, except using 2-bromo-m-xylene; (749mg, 76%):

m.p. 92-96° C. (CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3451, 2970, 1690, 1631,1425, 1165; Anal.Calcd.for C₃₀H₄₂N₂O₄.0.50H₂O: C, 71.54; H, 8.61; N,5.56. Found: C, 71.70; H, 8.34; N, 5.62; δ_(H) (400 MHz, CDCl₃) 1.10(brs, 3H), 1.21 (brs, 3H), 1.32 (m, 2H), 1.43 (s, 9H), 1.69 (m, 1H),1.77 (m, 1H), 2.32 (s, 6H), 2.47 (s, 1H), 2.75 (m, 3H), 3.25 (brs, 2H),3.51 (brs, 2H), 4.13 (brs, 2H), 6.91 (m, 2H), 7.00 (m, 1H), 7.26 (d,J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H); δ_(C-13) (100 MHz, CDCl₃) δ:12.6, 14.0, 25.0, 27.7, 28.2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0,125.8, 126.3, 127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7.

EXAMPLE 1 Preparation ofN,N-Diethyl-4-(phenyl-piperidin-4-ylidene-methyl)-benzamide (Compound 6)

To a solution of4-(α-hydroxyl-α-(4-N-t-butoxylcarbonylpiperidinyl)-benzyl)-N,N-diethylbenzamide(932 mg, 2.0 mmol) in dry dichloromethane (10 mL) was addedtrifluoroacetic acid (10.0 mL) at r.t. The reaction mixture was stirredfor 16 h at r.t., and then condensed. The residue was dissolved in AcOEt(100 ml). The resulting solution was washed with 1 N NaOH solution,aqueous NH₄Cl solution and brine, dried over MgSO₄. Removal of solventsgave a crude product, which was purified by silica gel column elutingwith MeOH—CH₂Cl₂ (20:80) to provide(α-phenyl-α-(4-N′,N′-diethylaminocarbonylphenyl))-4-methylene-piperidine(compound 6), (632 mg, 91%):

δ_(H) (400 MHz, CDCl₃) 1.08 (brs, 3H), 1.17 (brs, 3H), 2.29 (m, 4H),2.86 (m, 4H), 2.94 (brs, 1H), 3.24 (brs, 2H), 3.47 (brs, 2H), 7.09 (m,4H), 7.15 (m, 1H), 7.24 (m, 4H); δ_(C-13) (100 MHz, CDCl₃) δ: 12.6,14.1, 32.7, 32.8, 39.1, 43.2, 47.9, 126.0, 126.4, 127.9, 129.6, 134.9,135.4, 135.9, 141.7, 143.2, 171.1.

HCl salt: m.p. 110-120° C.(AcOEt-Ether-CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3440,2970, 1617, 1438, 1289; Anal.Calcd.for C₂₃H₂₈N₂O.1.0 HCl. 0.50CH₂Cl₂.0.25H₂O: C, 65.35; H, 7.12; N, 6.49. Found: C, 65.14; H, 7.08; N, 6.55.

EXAMPLE 2 Preparation ofN,N-Diethyl-4-(1-naphtyl-piperidin-4-ylidene-methyl)-benzamide (Compound7)

Method as described for Example 1, using compound 4;(226 mg, 71%):

m.p. 80-85° C. (MeOH—CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3052, 2970, 1628, 1431,1286; Anal.Calcd.for C₂₇H₃₀N₂O . 0.20CH₂Cl₂: C, 78.62; H, 7.37; N, 6.74.Found: C, 78.63; H, 7.07; N, 6.54; δ_(H) (400 MHz, CDCl₃) 1.06 (brs,3H), 1.16 (brs, 3H), 2.00 (m, 2H), 2.53 (m, 2H), 2.64 (brs, NH), 2.77(m, 2H), 2.97 (m, 2H), 3.20 (brs, 2H), 3.47 (brs, 2H), 7.26 (m, 5H),7.43 (m, 3H), 7.74 (m, 2H), 8.0 (m, 1H); δ_(C-13) (100 MHz, CDCl₃) δ:12.8, 14.1, 32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5, 125.7, 125.8,126.1, 127.1, 127.2, 129.1, 131.9, 132.5, 133.8, 135.1, 138.3, 139.8,142.6, 171.1.

EXAMPLE 3 Preparation ofN,N-Diethyl-4-(2,6-dimethylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 8)

Method as described for Example 1, using compound 5 (242 mg, 80%).

Its HCl salt: Dec.≧115° C. (AcOEt-Ether-CH₂Cl₂); ν_(max) (KBr) cm⁻¹2970, 2725, 1590, 1464, 1290, 1101; Anal.Calcd.for C₂₅H₃₂N₂O. 1.0 HCl.0.50CH₂Cl₂. 0.5H₂O: C, 65.94; H, 7.60; N, 6.03. Found: C, 65.98; H,7.37; N, 5.81.

EXAMPLE 4 Preparation ofN,N-Diethyl-4-(1-naphtyl-N-allyl-piperidin-4-ylidene-methyl)-benzamide(Compound 9)

A mixture of(α-(1-Naphthyl)-α-(4-N′,N′-diethylaminocarbonylphenyl))-4-methylene-piperidine(compound 7) (125 mg), allyl bromide (90 mg) and K₂CO₃ (138 mg) in MeCN(10 mL) was stirred for 14 hr at r.t., and then quenched with 1 N NH₄OHsolution, extracted with AcOEt (100 ml). The organic phase was washedwith aqueous NH₄Cl solution and brine, dried over MgSO₄. Removal ofsolvents gave a crude product, which was purified by silica gel columneluting with MeOH—CH₂Cl₂ (2:98) to provide(α-(1-naphthyl)-α-(4-N′,N′-diethylaminocarbonylphenyl))-4-methylene-N-allylpiperidine(50 mg, 36%):

δ_(H) (400 MHz, CDCl₃) 1.08 (brs, 3H), 1.19 (brs, 3H), 2.08 (m, 2H),2.39 (m, 2H), 2.61 (m, 4H), 3.01 (m, 2H), 3.24 (brs, 2H), 3.52 (brs,2H), 5.13 (m, 2H), 5.90 (m, 1H), 7.27 (m, 5H), 7.45 (m, 3H), 7.80 (m,2H), 8.04 (m, 1H); δ_(C-13) (100 MHz, CDCl₃) δ: 12.8, 14.1, 30.9, 32.0,39.1, 43.2, 54.7, 54.9, 61.5, 117.8, 125.4, 125.6, 125.8, 126.0, 127.1,128.2, 129.1, 131.8, 132.4, 133.7, 135.0, 138.0, 139.8, 142.6, 171.1.

Its HCl salt: m.p. 110-120° C. (AcOEt-Ether-CH₂Cl₂); ν_(max) (KBr) cm⁻¹3416, 2961, 1620, 1430, 1288; Anal.Calcd.for C₃₀H₃₄N₂O. 1.0 HCl.0.50CH₂Cl₂, 0.25H₂O; C, 70.17; H, 7.05; N, 5.37. Found: C, 70.15; H,6.92; N, 5.24.

EXAMPLE 5 Preparation ofN,N-Diethyl-4-(phenyl-N-benzyl-piperidin-4-ylidene-methyl)-benzamide(Compound 10)

Method as described for Example 4, using compound 6 and benzyl bromide(215 mg, 98%);

δ_(H) (400 MHz, CDCl₃) 1.09 (brs, 3H), 1.19 (brs, 3H), 2.37 (m, 4H),2.47 (m, 4H), 3.25 (brs, 2H), 3.50 (brs, 4H), 7.0-7.30 (m, 14 H);δ_(C-13) (100 MHz, CDCl₃) δ: 12.7, 14.0, 31.6, 39.1, 43.1, 54.9, 55.0,62.8, 125.9, 126.2, 126.8, 127.8, 128.0, 128.9, 129.6, 129.7, 134.9,135.0, 136.3, 138.2, 141.9, 143.3, 171.0.

Its HCl salt: m.p. 230-245° C. (AcOEt-Ether-CH₂Cl₂); ν_(max) (KBr) cm⁻¹3423, 2976, 1624, 1434, 1288; Anal.Calcd.for C₃₀H₃₄N₂O. 1.0 HCl.0.25CH₂Cl₂. 0.25H₂O: C, 72.55; H, 7.25; N, 5.59. Found: C, 72.38; H,7.16; N, 5.50.

EXAMPLE 6 Preparation ofN,N-Diethyl-4-(N-2,3-epoxypropyy-phenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 11)

Method as described for Example 4, using compound 6 and epibromohydrin(102 mg, 84%):

δ_(H) (400 MHz, CDCl₃) 1.10 (brs, 3H), 1.20 (brs, 3H), 2.28 (m, 1H),2.39 (m, 4H), 2.45 (m, 1H), 2.54 (m, 2H), 2.61 (m, 2H), 2.74 (m, 2H),3.09 (m, 1H), 3.26 (brs, 2H), 3.50 (brs, 2H), 7.10 (m, 4H), 7.15 (m,1H), 7.25 (m, 4H); δ_(C-13) (100 MHz, CDCl₃) δ: 12.8, 14.1, 31.4, 39.1,43.2, 44.9, 50.1, 55.5, 60.8, 126.0, 126.4, 127.9, 129.6, 129.7, 135.0,135.3, 135.7, 141.8, 143.2, 171.1.

EXAMPLE 7 Preparation ofN,N-Diethyl-4-(1-cyclopropylmethyl-phenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 12)

Method as described for Example 4, using compound 6 andcyclopropylmethyl chloride (104 mg, 86%):

δ_(H) (400 MHz, CDCl₃) 0.20 (m, 2H), 0.59 (m, 2H), 1.04 (m, 1H), 1.14brs, 3H), 1.24 (brs, 3H), 2.48 (d, J=6.4 Hz, 2H), 2.56 (brs, 4H), 2.80(brs, 4H), 3.29 (brs, 2H), 3.53 (brs, 2H), 7.14 (m, 4H), 7.22 (m, 1H),7.27 (m, 4H); δ_(C-13) (100 MHz, CDCl₃) δ: 4.18, 7.3, 12.8, 14.1, 30.3,39.2, 43.2, 54.3, 62.7, 126.2, 126.6, 128.0, 129.5, 129.6, 134.1, 135.3,136.3, 141.5, 142.9, 171.0.

Its HCl salt: Dec.≧100° C.(AcOEt-Ether-CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3027,2359, 1620, 1439, 958; Anal.Calcd.for C₂₇H₃₄N₂O. 1.0 HCl. 0.50CH₂Cl₂.0.75H₂O: C, 66.73; H, 7.64; N, 5.66. Found: C, 66.60; H, 7.45; N, 5.78.

B) Synthetic Scheme For the Preparation of the Compound of Example 8

The compound of Example 8 was prepared by following the procedure as isshown in Scheme 2 below.

(i) Preparation of 4-(2-Benzofuroyl)-N-t-butoxylcarbonylpiperidine(Compound 13)

To a solution of 2,3-benzofuran (295 mg, 2.5 mmol) in dry THF (10 mL)was added t-butyllithium (1.5 mL, 1.7 M, 2.5 mmol) at −78° C. After 30min, N-t-butoxylcarbonyl N-methyl-N-methoxyl-isonipecotamide (544 mg,2.0 mmol) in THF (2 mL) was dropwise added. the reaction mixture waswarmed to r.t. and then quenched with aqueous NH₄Cl solution, andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine, dried over MgSO₄. Removal of solvents gave a crudeproduct, which was purified by silica gel column eluting withMeOH-CH₂Cl₂ (5:95) to provide4-(2-benzofuroyl)-N-t-butoxylcarbonylpiperidine (13) (456 mg, 69%):

δ_(H) (400 MHz, CDCl₃) 1.46 (s, 9H), 1.75 (m, 2H), 1.91 (m, 2H), 2.91(m, 2H), 3.37 (m, 1H), 4.20 (brs, 2H), 7.29 (m, 1H), 7.46 (m, 1H), 7.53(s, 1H), 7.56 (m, 1H), 7.69 (m, 1H); δ_(C-13) (100 MHz, CDCl₃) δ: 27.8,28.3, 43.1, 44.4, 79.5, 112.3, 112.9, 123.1, 123.8, 126.9, 128.2, 151.8,154.5, 155.5, 192.8.

(ii) Preparation of4-(α-Hydroxy-α-(4-N-t-butoxylcarbonylpiperidinyl)-2-benzofuryl)-N,N-diethylbenzamide(Compound 14)

Method as described for compound 4, using 4-iodo-N,N-diethylbenzamide(425 mg, 61%):

m.p. 102-106° C. (CH₂Cl₂);

ν_(max) (KBr) cm⁻¹ 3362, 2970, 1690, 1617, 1425, 1288, 1160; δ_(H) (400MHz, CDCl₃) 1.06 (brs, 3H), 1.20 (brs, 3H), 1.24 (m, 2H), 1.46 (m, 11H),2.42 (m, 1H), 2.58 (brs, 2H), 3.20 (brs, 2H), 3.50 (brs, 2H), 4.05 (brs,2H), 4.37 (s, 1H), 6.70 (s, 1H), 7.16 (m, 2H), 7.23 (d, J=8.0 Hz, 2H),7.41 (d, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H);δ_(C-13) (100 MHz, CDCl₃) δ: 12.6, 13.9, 25.5, 26.3, 28.2, 39.0, 43.1,44.9, 77.3, 79.0, 103.3, 110.9, 120.6, 122.5, 123.5, 125.6, 125.8,127.9, 135.3, 144.0, 154.4, 154.5, 160.5, 170.9.

EXAMPLE 8 Preparation ofN,N-Diethyl-4-(2-benzofuryl-piperidin-4-ylidene-methyl)-benzamide(Compound 15)

Method as described for Example 1, using compound 14 (135 mg, 88%):

δ_(H) (400 MHz, CDCl₃) 1.20 (brs, 3H), 1.24 (brs, 3H), 2.36 (brs, 2H),3.00 (brs, 4H), 3.15 (brs, 2H), 3.33 (brs, 2H), 3.56 (brs, 2H), 4.45(brs, 1H), 6.25 (s, 1H), 7.24 (m, 4H), 7.41 (m, 4H); δ_(C-13) (100 MHz,CDCl₃) δ: 12.9, 14.2, 29.6, 32.0, 32.4, 39.3, 43.4, 47.2, 107.4, 111.0,120.7, 122.7, 124.2, 126.0, 126.5, 128.2, 129.9, 136.1, 139.5, 140.5,154.4, 156.2, 171.0.

Its HCl salt: Dec.≧120° C.(AcOEt-Ether-CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 2977,2801, 1586, 1449, 1257.

C) Synthetic Scheme For the Preparation of the Compounds of Examples9-10

The compounds of Examples 9 and 10 were prepared by following theprocedure of Scheme 3 below.

(i) Preparation of 4-(4-Fluorobenzoyl)-N-t-butoxylcarbonylpiperidine(Compound 18)

A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (compound 16)(2.44 g, 10.0 mmol), Di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) andNa₂CO₃ (1.59 g, 15 mmol) in H2O-THF (50/5 mL) was refluxed for 1 h. Thereaction mixture was extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with brine, dried over MgSO₄.Removal of solvents gave4-(4-fluorobenzoyl)-N-t-butoxylcarbonylpiperidine (OB 701-31, 2.28 g,74%);

m.p. 80-83° C. (CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 2980, 2842, 1680, 1587,1416, 1160; δ_(H) (400 MHz, CDCl₃) 1.44 (s, 9H), 1.69 (m, 2H), 1.79 (m,2H), 2.87 (m, 2H), 3.34 (m, 1H), 4.13 (brs, 2H), 7.12 (m, 2H), 7.95 (m,2H); δ_(C-13) (100 MHz, CDCl₃) δ: 27.4, 28.4, 43.2, 43.4, 79.6, 115.8,115.9, 130.8, 130.9, 132.2, 154.6, 164.4, 166.9, 200.4.

(ii) Preparation of 4-(4-Chlorobenzoyl)-N-t-butoxylcarbonylpiperidine(Compound 19)

Method as described for compound 18, using compound 17 (1.23 g, 85%):

m.p. 122-125° C. (CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 2970, 2842, 1680, 1582,1420, 1200; δ_(H) (400 MHz, CDCl₃) 1.47(s, 9H), 1.69 (m, 2H), 1.81 (m,2H), 2.90 (m, 2H), 3.36 (m, 1H), 4.18 (brs, 2H), 7.44 (m, 2H), 7.88 (m,2H); δ_(C-13) (100 MHz, CDCl₃) δ: 28.3, 28.4, 43.2, 43.4, 79.6, 129.0,129.6, 134.1, 139.4, 154.6, 200.7.

(iii) Preparation of4-(α-Hydroxy-α-(4-N-t-butoxylcarbonylpiperidinyl)-4-fluorobenzyl)-N,N-diethylbenzamide(Compound 20)

Method as described for compound 4, using compound 18 and4-iodo-N,N-diethylbenzamide (454 mg, 47%):

m.p. 84-86° C. (CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3421, 2970, 1685, 1612,1430, 1288, 1165; δ_(H) (400 MHz, CDCl₃) 1.13 (brs, 3H), 1.23 (brs, 3H),1.32 (m, 4H), 1.44 (s, 9H), 2.48 (m, 1H), 2.68 (brs, 2H), 3.26 (brs,2H), 3.54 (brs, 2H), 3.57 (s, 1H), 4.11 (brs, 2H), 6.96 (m, 2H), 7.27(d, J=8.0 Hz, 2H), 7.44 (m, 2H), 7.47 (d, J=8.0 Hz, 2H); δ_(C-13) (100MHz, CDCl₃) δ: 12.9, 14.0, 26.2, 28.2, 39.1, 43.2, 43.6, 44.3, 78.9,79.1, 114.5, 114.7, 125.7, 126.1, 127.5, 127.6, 135.0, 141.2, 146.9,154.5, 160.0, 162.5, 170.9.

(iv) Preparation of4-(α-Hydroxy-α-(4-N-t-butoxylcarbonylpiperidinyl)-4-chlorobenzyl)-N,N-diethylbenzamide(Compound 21)

Method as described for compound 4, using compound 19 and4-iodo-N,N-diethylbenzamide (626 mg, 63%):

m.p. 100-105° C. (CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3411, 2970, 1685, 1617,1425, 1288, 1165, 1092; δ_(H) (400 MHz, CDCl₃) 1.08 (brs, 3H), 1.20(brs, 3H), 1.33 (m, 4H), 1.41 (s, 9H), 2.44 (m, 1H), 2.63 (brs, 2H),3.22 (brs, 2H), 3.49 (brs, 2H), 3.99 (s, 1H), 4.05 (m, 2H), 7.20 (m,4H), 7.39 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H); δ_(C-13) (100 MHz,CDCl₃) δ: 12.5, 13.9, 25.9, 28.1, 39.0, 43.0, 44.1, 78.7, 79.0, 125.6,126.0, 127.2, 127.8, 131.9, 134.8, 144.1, 146.6, 154.3, 170.7.

EXAMPLE 9 Preparation ofN,N-Diethyl-4-(4-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 22)

Method as described for Example 1 (compound 6), using compound 20.

¹H-NMR (400 MHz, CDCl₃) δ 1.12 (3H, br m, CH ₃CH₂—), 1.24 (3H, br m, CH₃CH₂—), 2.32 (4H, m, piperidine CH—), 2.54 (1H, br m, NH), 2.91 (4H, m.piperidine CH—), 3.27 (2H, br m, CH ₂N—), 3.52 (2H, br m, CH ₂N—), 7.00(2H, m, ArH, 7.09 (2H, m, ArH), 7.11 (2H, d, J=8.0 Hz, ArH), 7.29 (2H,d, J=8.0 Hz, ArH).

EXAMPLE 10 Preparation ofN,N-Diethyl-4-(4-chlorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 23)

Method as described for Example 1 (compound 6), using compound 21.

¹H-NMR (400 MHz, CDCl₃) δ 1.13 (3H, br m, CH ₃CH₂—), 1.22 (3H, br m, CH₃CH₂—), 2.02 (1H, br m, NH), 2.30 (4H, m, piperidine CH—), 2.90 (4H, m,piperidine CH—), 3.28 (2H, br m, CH ₂N—), 3.53 (2H, br m, CH ₂N—), 7.04(2H, d, J=8.0 Hz, ArH), 7.11 (2H, d, J=8.0 Hz, ArH), 7.25 (2H, d, J=8.0Hz, ArH), 7.30 (2H, d, J=8.0 Hz, ArH).

Its HCl salt: m.p. 115-120° C. (H₂O—CH₂Cl₂); IR (KBr) 3337, 2973, 1618,1431, 1290, 1092 cm⁻¹; Anal. Calcd. for C₂₃H₂₇ClN₂O.1.0OHCl.1.20H₂O: C,62.64%; H, 6.95%; N, 6.35%; Found: C, 62.53%; H, 6.91%; N, 6.30%.

D) Synthetic Scheme For the Preparation of the Compound of Example 11

EXAMPLE 11 Preparation ofN,N-Diethyl-4-(phenyl-N-allyl-piperidin-4-ylidene-methyl)-benzamide(Compound 25)

4-(α-hydroxy-α-(4-N-allylpiperidinyl)-benzyl)-N,N-diethylbenzamide(compound 24) (81 mg) was dissolved in CH₂Cl₂ (10 ml) and was treatedwith thionyl chloride (2 ml) at r.t. The reaction mixture was refluxedfor 2 hrs, and then condensed. The residue was dissolved in ethylacetate (50 mL) and the resulting solution was washed with NH₄OH (1 N),aqueous NH₄Cl solution and brine, dried over MgSO₄. Removal of solventsgave a crude product, which was purified by silica gel column elutingwith MeOH—CH₂Cl₂ (1:99→5:95) to provide(α-phenyl-α-(4-N′,N′-diethylaminocarbonylphenyl))-4-methylene-N-allylpiperidine(compound 25; Example 11) (32 mg, 40%):

δ_(H)(400 MHz, CDCl₃) 1.12 (brs, 3H), 1.21 (brs, 3H), 2.43 (m, 4H), 2.55(m, 4H), 3.08 (d, J=6.8 Hz, 2H), 3.25 (brs, 2H), 3.53 (brs, 2H), 5.18(m, 2H), 5.86 (m, 1H), 7.12 (m, 4H), 7.20 (m, 1H), 7.27 (m, 4H).

Its HCl salt: m.p. 85-95° C. (AcOEt—CH₂Cl₂); ν_(max) (KBr) cm⁻¹ 3491,2971, 1624, 1428, 1289, 1096; Anal.Calcd.for C₂₆H₃₂N₂O.HCl. 0.25 H₂O.0.25CH₂Cl₂: C, 69.95; H, 7.60; N, 6.21. Found: C, 70.00; H, 7.73; N,6.07.

EXAMPLE 12 Preparation ofN,N-Diethyl-4-(4-chlorophenyl-N-benzyl-piperdin-4-ylidene-methyl)-benzamide(Compound 26)

Method as described for Example 4, using compound 23 (96 mg) and benzylbromide (43 mg) providedN,N-diethyl-4-(4-chlorophenyl-N-benzyl-piperidin-4-ylidene-methyl)-benzamide(110 mg, 93%):

¹H-NMR (400 MHz, CDCl₃) δ 1.13 (3H, br m, CH ₃CH₂—), 1.23 (3H, br m, CH₃CH₂—), 2.37 (4H, m, piperidine CH—), 2.49 (4H, m, piperidine CH—), 3.28(2H, br m, CH₃CH ₂N—), 3.53 (4H, br m, PhCH ₂N and CH₃CH ₂N—), 7.04 (2H,d, J=8.0 Hz, ArH), 7.11 (2H, d, J=8.0 Hz, ArH), 7.25 (2H, d, J=8.0 Hz,ArH), 7.29 (7H, m, ArH).

Its (CHOHCO₂H)₂ salt: m.p. 100-110° C. (MeOH); IR (KBr) 3368, 2977,1728, 1603, 1433, 1290, 1087 cm⁻¹; Anal.Calcd.for C₃₄H₃₉ClN₂O₇.1.50H₂O:C, 62.81%; H, 6.51%; N, 4.31%; Found: C, 62.85%; H, 6.17%; N, 4.21%.

EXAMPLE 13 Preparation ofN,N-Diethyl-4-[(N-3-methyl-2-butenyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide(Compound 27)

Method as described for example 4, using 1-Bromo-3-methyl-2-butene asthe alkylating reagent.

IR (NaCl Film): HCl salt ν=3432, 2976, 1623, 1434, cm⁻¹.

¹H NMR: (Base) (CDCl₃, TMS) δ: 1.10˜1.30 (6H, br, OCNCH₂CH₃ ), 1.64 (3H,s, ═CCH₃ ), 1.73 (3H, s, ═CCH₃ ), 2.40 (4H, m, NCH₂ CH₂), 2.52 (4H, m,═CCH₂ ), 3.0 (2H, d, J=7.6 Hz, NCH₂ CH═C), 3.20˜3.60 (4H, br, OCNCH₂CH₃),. 5.28 (1H, m, NCH ₂ CH═C), 7.16˜7.45(9H, m, Ar)ppm.

ANALYSIS: (%) Anal.Calcd.for:: C₂₈H₃₆N₂O. 1.8HCl: C, 69.74; H, 7.90; N,5.81. Found: C, 69.71; H, 7.48; N, 5.58.

EXAMPLE 14 Preparation ofN,N-diethyl-4-[(1-Cyclohexyl-piperidin-4-ylidene)-phenyl-methyl]-benzamide(Compound 28)

A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 ul, 0.35mmol) and Ti(OPr-i)₄ (0.17 ml, 0.58 mmol) was ultrasonicated for 1 hrand then stirred at rt overnight under a nitrogen atmosphere. Themixture was diluted with ethanol (5 ml) and followed by addition ofNaBH₄ (33 mg, 0.87 mmol). The resulting mixture was stirred for 12 hr atrt. 2N NH₃.H₂O was added to quench the reaction and the mixture filteredthrough celite. The filtrate was extracted with ethyl acetate severaltimes and the combined organic phases washed with water and brine, anddried over Na₂SO₄. Concentration in vacuo and MPLC purification (0::100to 100:0 EtOAc:Heptane eluting on silcal gel 60) gave the title compound(24 mg, 20%).

m.p. (HCl salt): 105-109° C. IR (HCl salt, film) ν: 3394 (NH), 1620(CONEt₂)cm⁻¹.

¹H NMR (free amine, 400 MHz, CDCl₃) δ: 1.00-1.25 (17H, m,NCHCH₂CH₂CH₂CH₂CH₂ , 2×CH₃ and CH(CH)C═C), 1.60 (1H, m, CH(CH)C═C), 1.75(1H, m, CH(CH)C═C), 1.80 (1H, m, CH(CH)C═C), 2.30 (3H, m, NCH₂ and NCH),2.60 (2H, m, NCH₂ ), 3.20 (2H, bs, NCH₂ CH₃), 3.50 (2H, bs, NCH₂ CH₃),7.00-7.30 (9H, m, Ar).

¹³C NMR (free amine, 100 MHz, CDCl₃) δ: 12.7, 14.1, 25.9, 28.7, 32.0,39.1, 43.2, 50.7, 50.8, 63.6, 126.0, 126.3, 127.9, 129.7, 129.8, 134.7,134.9, 136.9, 142.0, 143.4, 171.2. Elemental analysis: Calcd.forC₂₉H₄₀N₂OCl₂: C, 69.17; H, 8.01; N, 5.56. Found: C, 69.17; H, 7.82; N,5.18.

EXAMPLE 15 Preparation ofN,N-Diethyl-4-[(N-butyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide(Compound 29)

Method as described for Example 4, using 1-Iodobutane as the alkylatingreagent. IR (NaCl Film):(HCl salt) ν=3430, 2967, 2499, 1622, 1433 cm⁻¹

¹H NMR: (CDCl₃, TMS) δ: 0.92 (3H, t, J=7.2 Hz, CH₂CH₃ ), 1.10˜1.26 (6H,br, OCNCH₂CH₃ ), 1.32 (2H, m, CH2CH3), 1.53 (2H, m, CH2CH2CH2), 2.42(6H, m NCH2), 2.55 (4H, m, ═CCH2), 3.20˜3.60 (4H, br, OCNCH₂ CH₃),7.10˜7.31 (9H, m Ar)ppm. ANALYSIS: (%) Anal.Calcd.for:C₂₇H₃₆N₂O.HCl.0.4CH₂Cl₂.0.4H₂O: C, 68.24; H, 8.07; N, 5.81. Found: C,68.24; H, 8.12; N, 5.89.

EXAMPLE 16 Preparation ofN,N-Diethyl-4-[(N-4-methoxybenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide(Compound 30)

Method as described for Example 4, using compound 6 (174 mg) and4-methoxybenzyl chloride (78 mg) providedN,N-diethyl-4-[(N-4-methoxybenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide(160 mg, 68%):

¹H-NMR (400 MHz, CDCl₃) δ 1.11 (3H, br, CH ₃CH₂N—), 1.20 (3H, br, CH₃CH₂N—), 2.38 (4H, m, CCH ₂C), 2.46 (4H, m, NCH ₂—), 3.26 (2H, m, NCH₂—), 3.47 (2H, s, CH ₂N—), 3.49 (2H, br, CH₃CH ₂N—), 3.77 (3H, s, OCH₃), 6.83 (2H, d, J=8.0 Hz, ArH), 7.05-7.30 (11H, m, ArH).

Its HCl salt: m.p. 100-110° C. (CH₂Cl₂); IR (KBr) 3425, 2974, 1618,1515, 1434, 1255 cm⁻¹; Anal.Calcd.for C₃₁H₃₆N₂O₂.1.0HCl 0.35CH₂Cl₂: C,70.41%; H, 7.11%; N, 5.24%; Found: C, 70.46%; H, 7.10%; N, 5.21%.

EXAMPLE 17 Preparation ofN,N-Diethyl-4-[(N-2,4-dichlorobenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide(Compound 31)

Method as described for Example 4, using compound 6 (174 mg) andα,2,4-trichlorotoluene(98 mg) providedN,N-diethyl-4-[(N-2,4-dichlorobenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide(206 mg, 81%):

¹H-NMR (400 MHz, CDCl₃) δ 1.12 (3H, br, CH ₃CH₂N—), 1.21 (3H, br, CH₃CH₂N—), 2.39 (4H, m, CCH ₂C), 2.52 (4H, m, NCH ₂—), 3.28 (2H, m, NCH₂—), 3.53 (2H, br, CH₃CH ₂N—), 3.57 (2H, m, NCH ₂—), 7.05-7.48 (12H, m,ArH).

Its HCl salt: m.p. 95-110° C. (CH₂Cl₂); IR (KBr) 3408, 2976, 1620, 1472,1436, 1288, 1101 cm⁻¹; Anal.Calcd.for C₃₀H₃₂N₂OCl₂.1.0HCl 0.30CH₂Cl₂: C,63.91%; H, 5.95%; N, 4.92%, Found: C, 63.81%; H, 6.03%; N, 4.84%.

EXAMPLE 18 Preparation ofN,N-Diethyl-4-[(1-methyl-piperidin-4-ylidene)-phenyl-methyl]-benzamide(Compound 32)

N,N-Diethyl-4-[(piperidin-4-ylidene)-phenyl-methyl]-benzamide (0.34 g,1.0 mmol) was disolved in acetonitrile (5 mL). Potassium carbonate (0.14g, 1.0 mmol) and methyl iodide (63 μL, 1.0 mmol) was added with stirringat 25° C. After 30 min., the reaction mixture was evaporated and putonto silica gel for purification by chromatography using 0 to 10%MeOH(10% NH₄OH) in CH₂Cl₂ to give 48 mg of the final product (28% ofconverted starting material), which was converted to the hydrochloridesalt by treatment with HCl in ether.

Mp: 110° C. (dec.). IR (KBr) (cm-1): 2361, 1695, 1487, 1289. MS(freeamine): 362, 318, 219, 189, 165, 144. ¹H NMR: (amine, CDCl₃): δ=1.1(m,6H, amide-Me), 2.40 (s, 3H, MeN), 2.49, 2.60 (2m, 8H, piperazine-H),3.40 (m, 4H, amide-CH₂) 7.08-7.34 (m, 9H, Ar—H). C₂₄H₃₀N₂O×0.1 H₂O×3.1HCl, requires: C:60.39, H:7.03, N:5.87. Found C:60.43, H:6.84, N:5.45.

EXAMPLE 19 Preparation ofN,N-Diethyl-4-[(N-tert-butoxycarbonyl-piperidin-4-yl)-8-quinolinyl-hydroxy-methyl]-benzamide(Compound 33)

To a solution of 4-iodo-N,N-diethylbenzamide (1.52 g, 5.0 mmol) and8-bromoquinoline (1.0 g) in dry THF (30 mL) was added n-butyllithium(7.0 mL, 2.5 M, 17.5 mmol) at −78° C. After 10 min, N-t-butoxylcarbonylethyl isonipecotate (2) (0.77 g, 3.0 mmol) in THF (5 mL) was dropwiseadded. The reaction mixture was warmed to ° C., and then quenched withaqueous NH₄Cl solution, and extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with brine, dried over MgSO₄.Removal of solvents gave a crude product, which was purified by silicagel column eluting with MeOH—CH₂Cl₂ (2:98) to MTL 0599 (145 mg, 9%):

m.p. 100-105° C.; IR (NaCl) 2971, 1686, 1625, 1426, 1167 cm⁻¹;Anal.Calcd.for C₃₁H₃₉N₃O₄.0.20H₂O: C, 71.43%; H, 7.62%. Found: C,71.50%; H, 7.75%; ¹H-NMR (400 MHz, CDCl₃) δ 1.07 (3H, br, CH ₃CH₂N—),1.19 (3H, br, CH ₃CH₂N—), 1.24 (1H, m, piperidine CH—), 1.43 (9H, s, CH₃C), 1.65 (1H, m, piperidine CH—), 1.89 (2H, m, piperidine CH—), 2.52(1H, m, piperidine CH—), 2.64 (1H, br, piperidine CH—), 2.78 (1H, br,piperidine CH—), 3.22 (2H, br, CH₃CH ₂N—), 3.49 (2H, br, CH₃CH ₂N—),4.16 (2H, br, piperidine CH—), 7.24 (2H, d, J=8.0 Hz, ArH), 7.35 (1H,dd, J=8.0, 4.4 Hz, ArH), 7.55 (2H, d, J=8.0 Hz, ArH), 7.58 (1H, d, J=8.0Hz, ArH), 7.71 (1H, d, J=8.0 Hz, ArH), 7.80 (1H, d, J=8.0 Hz, ArH), 8.14(1H, d, J=8.0 Hz, ArH), 8.69 (1H, m, ArH), 9.80 (1H, s, OH).

EXAMPLE 20 Preparation ofN,N-Diethyl-4-(8-quinolinyl-piperidin-4-ylidene-methyl)-benzamide(Compound 34)

A mixture of the compound of Example 19 (45 mg), trifluoroacetic acid(1.0 mL) and trifluoromethanesulforic acid (1 mL) was refluxed for 8hrs., and then condensed. The residue was dissolved in AcOEt (50 ml).The resulting solution was washed with 1 N NaOH solution, aqueous NH₄Clsolution and brine, dried over Na₂SO₄. Removal of solvents gave a crudeproduct, which was purified by silica gel column eluting with NH₄OH(1N)-MeOH—CH₂Cl₂ (2.5:17.5:80) to provideN,N-diethyl-4-(8-quinolinyl-piperidin-4-ylidene-methyl)-benzamide (29mg, 84%):

¹H-NMR (400 MHz, CDCl₃) δ 1.07 (3H, br m, CH ₃CH₂—), 1.20 (3H, br m, CH₃CH₂—), 2.00 (2H, m, piperidine CH—), 2.46 (1H, s, NH), 2.52 (2H, m,piperidine CH—), 2.75 (1H, m, piperidine CH—), 2.92 (2H, m, piperidineCH—), 3.05 (1H, m, piperidine CH—), 3.22 (2H, m, CH ₂N—), 3.49 (2H, m,CH ₂N—), 7.23 (2H, m, ArH), 7.32 (2H, m, ArH), 7.36 (1H, m, ArH), 7.49(2H, m, ArH), 7.72 (1H, dd, J=6.4, 3.2 Hz, ArH), 8.11 (1H, dd, J=8.4,1.6 Hz, ArH), 8.91 (1H, dd, J=4.0, 1.6 Hz, ArH).

Its HCl salt: m.p.>170° C. (Dec.); IR (KBr) 3410, 2973, 1614, 1551,1436, 1284 cm⁻¹; Anal.Calcd.for C₂₆H₂₉N₃O. 2.0 HCl. 0.50 CH₂Cl₂. 0.75H₂O: C, 60.23%; H, 6.39%; Found: C, 60.27%; H, 6.42%.

EXAMPLE 21 Preparation ofN,N-Diethyl-4-[(N-tert-butoxycarbonyl-piperidin-4-yl)-3-methoxyphenyl-hydroxy-methyl]-benzamide(Compound 35)

Method as for Example 19 using 3-bromoanisole provided the titlecompound (226 mg, 23%):

m.p.95-103° C.; IR (NaCl) 3422, 2973, 1684, 1614, 1429, 1289 cm⁻¹;Anal.Calcd.for C₂₉H₄₀N₂O₅.0.60H₂O: C, 68.64%; H, 8.18%; N, 5.52%. Found:C, 68.66%; H, 7.98%; N, 5.64%; ¹H-NMR (400 MHz, CDCl₃) δ 1.07 (3H, br,CH ₃CH₂N—), 1.19 (3H, br, CH ₃CH₂N—), 1.31 (4H, m, piperidine CH—), 1.41(9H, s, CH,C), 2.46 (1H, m, piperidine CH—), 2.64 (2H, br, piperidineCH—), 3.22 (2H, br, CH₃CH ₂N—), 3.49 (2H, br, CH₃CH ₂N—), 3.65 (1H, s,OH), 3.72 (3H, s, OCH ₃), 4.06 (2H, br, piperidine CH—), 6.69 (1H, m,ArH), 7.01 (1H, d, J=7.6 Hz, ArH), 7.08 (1H, s, ArH), 7.17 (1H, d, J=8.0Hz, ArH), 7.21 (2H, d, J=8.0 Hz, ArH), 7.48 (2H, d, J=8.0 Hz, ArH).

EXAMPLE 22 Preparation ofN,N-Diethyl-4-(3-methoxyphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 36)

Method as described for Example 1, using the compound of Example 21 (100mg) providedN,N-diethyl-4-(3-methoxyphenyl-piperidin-4-ylidene-methyl)-benzamide (75mg, 98%):

¹H-NMR (400 MHz, CDCl₃) δ 1.12 (3H, br, CH ₃CH₂N—), 1.23 (3H, br, CH₃CH₂N—), 2.34 (4H, m, piperidine CH—), 2.91 (4H, br, piperidine CH—),3.17 (1H, s, NH), 3.27 (2H, br, CH₃CH ₂N—), 3.52 (2H, br, CH₃CH ₂N—),3.76 (3H, s, OCH ₃), 6.64 (1H, s, ArH), 6.70 (1H, d, J=8.0 Hz, ArH),6.76 (1H, d, J=7.6 Hz, ArH), 7.15 (2H, d, J=8.0 Hz, ArH), 7.22 (1H, m,ArH), 7.29 (2H, d, J=8.0 Hz, ArH).

Its HCl salt: m.p.>90° C. (Dec); IR (NaCl) 2970, 1621, 1430, 1287 cm⁻¹;Anal.Calcd.for C₂₄H₃₀N₂O₂.HCl.1.70H₂O: C, 64.69%; H, 7.78%; N, 6.29%;Found: C, 64.82%; H, 7.60%; N, 6.08%

EXAMPLE 23 Preparation ofN,N-Diethyl-4-[(N-benzyl)-3-methoxyphenyl-piperidin-4-ylidene-methyl]-benzamide(Compound 37)

Method as for Example 4, using the compound of Example 22 (38 mg)providedN,N-diethyl-4-[(N-benzyl)-3-methoxyphenyl-piperidin-4-ylidene-methyl]-benzamide(46 mg, 98%):

¹H-NMR (400 MHz, CDCl₃) δ 1.12 (3H, br, CH ₃CH₂N—), 1.25 (3H, br, CH₃CH₂N—), 2.38 (4H, m, piperidine CH—), 2.48 (4H, br, piperidine CH—),3.27 (2H, br, CH₃CH ₂N—), 3.52 (2H, s, Ph CH ₂N), 3.53 (2H, br, CH₃CH₂N—), 3.75 (3H, s, OCH ₃), 6.65 (1H, s, ArH), 6.69 (1H, d, J=8.0 Hz,ArH), 6.74 (1H, d, J=7.6 Hz, ArH), 7.13 (2H, d, J=8.0 Hz, ArH),7.13-7.32 (8H, m, ArH).

Its HCl salt: m.p. 100-110° C. (CH₂Cl₂); IR (NaCl) 3421, 2972, 1619,1430, 1287 cm⁻¹; Anal.Calcd.for C₃₁H₃₆N₂O₂.HCl.0.40CH₂Cl₂: C, 69.96%; H,7.07%; N, 5.20%; Found: C, 69.94%; H, 7.06%; N, 5.15%.

EXAMPLE 24 Preparation ofN,N-Diethyl-4-[(N-tert-butoxycarbonyl-piperidin-4-yl)-3-fluorophenyl-hydroxy-methyl]-benzamide(Compound 38)

Method as for Example 19 using 3-bromofluorobenzene provided the titlecompound (257 mg, 27%):

¹H-NMR (400 MHz, CDCl₃) δ 1.03 (3H, br, CH ₃CH₂N—), 1.15 (3H, br, CH₃CH₂N—), 1.19-1.29 (4H, m, piperidine CH—), 1.35 (9H, s, CH ₃C), 2.39(1H, m, piperidine CH—), 2.59 (2H, br, piperidine CH—), 3.17 (2H, br,CH₃CHN—), 3.28 (1H, s, OH), 3.45 (2H, br, CH₃CH ₂N—), 4.02 (2H, br,piperidine CH—), 6.80 (1H, m, ArH), 7.15 (3H, m, ArH), 7.18 (2H, d,J=8.0 Hz, ArH), 7.39 (2H, d, J=8.0 Hz, ArH).

EXAMPLE 25 Preparation ofN,N-Diethyl-4-(3-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 39)

Method as for Example 20 using the compound of Example 24 (165 mg)providedN,N-Diethyl-4-(3-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide (108mg, 87%):

¹H-NMR (400 MHz, CDCl₃) δ 1.08 (3H, br, CH ₃CH₂N—), 1.19 (3H, br, CH₃CH₂N—), 2.09 (1H, s, NH), 2.25 (4H, m, piperidine CH—), 2.84 (4H, br,piperidine CH—), 3.23 (2H, br, CH₃CH ₂N—), 3.47 (2H, br, CH₃CH ₂N—),6.74 (1H, m, ArH), 6.86 (2H, m, ArH), 7.06 (2H, d, J=8.0 Hz, ArH), 7.18(1H, m, ArH), 7.24 (2H, d, J=8.0 Hz, ArH).

Its HCl salt: m.p.>70° C. (Dec.); IR (NaCl) 2978, 1605, 1478, 1432, 1290cm⁻¹; Anal.Calcd.for C₂₃H₂₇N₂OF.HCl.0.25 CH₂Cl₂.1.50 H₂O: C, 61.89%; H,7.04%; N, 6.21%; Found: C, 61.97%; H, 6.95%; N, 6.22%.

E) Synthetic Scheme For the Preparation of the Compound of Example 26

The compound of Example 26 was prepared by following the procedure as isshown in Scheme 5 below.

(i) Preparation of Preparation of 4′-Iodo-acetanilide (Compound 40)

To a solution of 4-Iodo-aniline (15 g, 69 mmol) in dry CH₂Cl₂ (100 ml)was added acetic anhydride(14.09 g, 138 mmol) at room temperature, thereaction mixture was then stirred for 2 hr. The gray color precipitateformed during the reaction was filtered, washed with ether andcollected, the mother solution was concentrated to dryness and AcOEt wasadded, the resulting precipitate was filtered, washed with ether andcombined with the previous solid as the desired product (15.95 g,88.7%).

¹H NMR: (CDCl₃) δ: 2.19 (3H, s, COCH ₃), 7.2 (1H, s, br, —NH), 7.23 (2H,m, Ar), 7.61 (2H, m, Ar)

(ii) Preparation of 4-(4-acetamidobenzoyl)-N-t-butoxylcarbonylpiperidine(Compound 41)

To a solution of 4′-iodo-acetanilide (11.7 g, 45 mmol) in dry THF (200ml) was added NaH (1.62 g, 67.5 mmol) at 0° C., the reaction mixture wasstirred for 30 min while temperature was warming up to room temperature,following by the slow addition of n-BuLi (1.6 M in Heptane, 54 mmol) at−78° C. The mixture was stirred for 15 min then N-t-ButoxylcarbonylN′-methyl-N′methoxyl-isonipecotamide(6.15 g, 30 mmol) in THF (10 ml) wasadded dropwise via syringe. The reaction mixture was warmed up to r.t.and then quenched with aqueous NH₄Cl solution, and extracted with ethylacetate (2×100 ml) The organic layer was washed with saturated(aq)NH₄Cl, brine, dried over MgSO₄ and concentrated to give a crudeproduct, which was further purified by silica gel column chromatographyusing MeOH—CH₂Cl₂ (0:100˜5:95) to provide the desired product (9.02 g,87%).

¹H NMR: (CDCl₃) δ: 1.47 (9H, s (CH₃)₃), 1.6-1.8 (4H, m, piperidine),2.21 (3H, s, COCH₃), 2.9 (2H, m, piperidine), 3.37 (1H, m, COCH—), 4.15(2H, m, piperidine), 7.64 (2H, m, Ar), 7.86 (1H, s, br, —CONH), 7.91(2H, m, Ar).

(iii) Preparation of4-((α-Hydroxy-α-(4-N-t-butoxylcarbonylpiperidinyl)-3-Fluorobenzyl)acetanilide (Compound 42)

Method as described for the preparation of compound 4 but substituting3-fluoro-1-iodobenzene for 1-bromonaphthalene to give the titlecompound. (93%)

¹H NMR: (DMSO-D₆) δ: 1.2-1.3 (4H, m, piperidine), 1.37 (9H, s, (CH₃)₃),2.0 (3H, s, COCH₃), 2.65 (3H, br, piperidine), 3.95 (2H, m, piperidine),6.98 (1H, m, Ar), 7.21-7.50 (7H, m, Ar), 9.85 (1H, s, OC—NH)

(iv) Preparation ofN-methyl-4-(α-Hydroxy-α-(4-N-t-butoxylcarbonylpiperidinyl)-3-Fluorobenzyl)acetanilide (Compound 43)

To a 2M (aq)NaOH solution (10 ml), tetrabutylammonium hydrogensulphate(1.35 g, 3.97 mmol) was added, followed by the addition of4-(α-Hydroxy-)-α-(4-N-t-butoxylcarbonylpiperidinyl)-3-fluorobenzyl)acetanilide(825 mg, 1.86 mmol) and methyl iodide (769 mg, 5.4 mmol) in 10 ml ofdichloromethane. The reaction mixture was then refluxed for 1 hr, cooleddown to r.t. The dichloromethane layer was collected and evaporated to˜1 ml. Ethyl acetate was added and the precipitate was filtered out. Theorganic phase was washed with brine and dried over MgSO4, concentratedto give a solid which was further purified by MPLC using MeOH—CH₂Cl₂(5:95) as to give the pure titled compound (770 mg, 93%).

¹H NMR: (CDCl₃) δ:1.2-1.5 (4H, m, piperidin), 1.42 (9H, s, (CH₃)₃), 1.83(3H, s, COCH ₃), 2.52 (1H, m, —CH—C—OH), 2.70 (2H, m, piperidine), 2.86(1H, s, br, —OH), 3.21 (3H, s, NCH ₃), 4.15 (2H, s, br, piperidine),6.90 (1H, m, Ar), 7.12-7.60 (7H, m, Ar).

EXAMPLE 26 Preparation ofN-methyl-4-(3-Fluorophenyl-piperidin-4-ylidenemethyl)acetanilide(Compound 44)

To a solution ofN-methyl-4-(α-Hydroxy-α-(4-N-t-butoxylcarbonylpiperidinyl)-3-fluorobenzyl)acetanilide (300 mg, 0.657 mmol) in dry dichloromethane (5 mL) was addedtrifluoroacetic acid (5.0 mL) at r.t. The reaction mixture was refluxedfor 4 hr., and then condensed. The residue was dissolved in AcOEt (50ml). The resulting solution was washed with 2 N (aq)NaOH, (aq) NH₄Cl andbrine, dried over MgSO₄. Removal of solvents gave a crude product, whichwas purified by MPLC eluting with MeOH—CH₂Cl₂-NH₄OH (5:95:1) to providethe pure product (176 mg, 79%). mp. 235˜237° C. dec.

IR (NaCl Film): (HCl salt) ν(max.)=2961, 2722, 2480, 1658, 1608, 1580,1507, 1429, 1381 cm⁻¹.

¹H NMR: (CDCl₃) δ: 1.89 (3H, s, COCH ₃), 1.95 (1H, s, —NH), 2.32(4H, m,piperazine), 2.92 (4H, m, piperazine), 3.26 (3H, s, N—CH ₃), 6.81-7.28(8H, m, Ar) ¹³C NMR:(CDCl₃) δ: 22.4, 33.2, 33.3, 37.0, 48.3, 113.3(m,C—F), 116.5(m, C—F), 125.4, 126.6, 129.5, 129.6, 130.9, 133.7, 137.7,141.2, 142.8, 144.2, 161.3, 163.8, 170.4. ANALYSIS: (%) Anal.Calcd.for:C₂₁H₂₃N₂FO.HCl: C, 67.28; H, 6.45; N, 7.47. Found: C, 66.88; H, 6.44; N,7.16.

F) Synthetic Scheme For the Preparation of the Compound of Example 27

The compound of Example 27 was prepared by following the procedure as isshown in Scheme 6 below.

(i) Preparation of N-tert-Butoxylcarbonyl-4-piperidone (Compound 46)

A mixture of compound 45 (50 g, 0.325 mol) and di-tert-butyl dicarbonate(71 g, 0.325 mol) in 300 mL of dichloromethane were stirred at 0° C.while triethylamine (133 g, 1.32 mol) was added dropwise. The mixturewas allowed to warm to room temperature and was stirred for 12 hrs. Thesolvent was evaporated and the crude product was partitioned betweenwater (400 mL) and diethyl ether (400 mL). The aqueous phase was washedwith an additional portion of diethyl ether (400 mL). The combined etherwas washed with water (400 mL) and brine (400 mL) dried over MgSO₄.Removal of solvent gave compound 46 as a pale yellow solid. (55.3 g,85%):

δ_(H)(400 MHz, CDCl₃) 1.50 (s, 9H), 2.45 (t, 4H, J=6.1 Hz), 3.72 (t, 4H,J=6.1 Hz)

(ii) Preparation of4-(4-Methoxycarbonyl-benzylidene)-piperidine-1-carboxylic acidtert-butyl ester (Compound 49)

Methyl 4-(bromomethyl) benzoate (compound 47) (11.2 g, 49 mmol) wasdissolved in 25 mL trimethyl phosphite and refluxed under N₂ for 5 hrs.Excess trimethyl phosphite was removed by co-distillation with tolueneto give crude 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester(compound 48).

δ_(H)(400 MHz, CDCl₃) 3.20 (d, 2H, J=22 Hz), 3.68 (d, 3H 10.8 Hz), 3.78(d, 3H, 11.2 Hz), 3.91 (s, 3H), 7.38 (m, 2H), 8.00 (d, 2H, J=8 Hz.

The crude product (compound 48) was dissolved in dry THF (200 mL) underN₂ and cooled to −78° C. Lithium diisopropylamide (32.7 mL 1.5 M inhexanes, 49 mmol) was added dropwise. The solution was allowed to warmto room temperature. A solution of compound 46 (9.76 g, 49 mmol in 100mL dry THF) was added to the reaction dropwise and was stirred under N₂for 12 hrs. Water (300 mL) and ethyl acetate (300 mL) were added to thereaction mixture and extracted. The aqueous phase was washed with ethylacetate (2×300 mL). The combined ethyl acetate was dried over MgSO₄ andevaporated to give a crude product, which was purified by silica gelchromatography (0-33% ethyl acetate in hexanes) to provide compound 49as a white solid (5.64 g, 35%).

δ_(H)(400 MHz, CDCl₃) 1.44 (s, 1H), 2.31 (t, J=5.5 Hz, 2H), 2.42 (t,J=5.5 Hz, 2H), 3.37 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.87(s,3H), 6.33 (s, 1H), 7.20 (d J=6.7 Hz, 2H), 7.94 (d, J=6.7 Hz, 2H).δ_(c-13) (CDCl₃) 28.3, 29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4,140.5, 142.1, 154.6, 166.8 ppm. ν_(max) (NaCl) cm⁻¹ 3424, 2974, 2855,1718, 1688, 1606, 1427, 1362, 1276.

Analysis calculated for C₁₉H₂₅NO₄: C 68.86%, H 7.60%, N 4.23%; actual: C69.1%, H7.69%, N 4.25%.

(iii) Preparation of4-Bromo-4-[bromo-(4-methoxycarbonyl-phenyl)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (Compound 50)

To a solution of compound 49 (5.2 g, 16 mmol) in dry dichloromethane(200 mL) was added K₂CO₃ (1.0 g). A bromine solution (2.9 g, 18 mmol in30 mL DCM) was then added dropwise at 0° C. and stirred for 1.5 hrs atroom temperature. The K₂CO₃ was removed by filtration and the solventwas evaporated to dryness. The crude product was dissolved in ethylacetate (200 mL) and washed with water (200 mL), 0.5 M HCl (200 mL) andbrine (200 mL), dried over MgSO₄. The solvent was evaporated to givecrude product which was recrystallized from methanol to give compound 50as a white solid (6.07 g, 78%).

δ_(H) (400 MHz, CDCl₃) 1.28 (s, 9H), 1.75 (m, 2H), 1.90 (m, 2H), 2.1 (m,4H), 3.08 (br, 4H), 3.90 (s, 3H), 4.08 (br, 4H), 5.14 (s, 1H), 7.57 (d,J=8.4 Hz, 2H) 7.98 (d, J=8.4 Hz, 2H). δ_(c-13) (400 MHz, CDCl₃) 28.3,36.6, 38.3, 40.3, 52.1, 63.2, 72.9, 129.0, 130.3, 130.4, 141.9, 154.4,166.3 ppm. ν_(max) (NaCl) cm⁻¹ 3425, 2969, 1725, 1669, 1426, 1365, 1279,1243.

Analysis calculated for: C₁₉H₂₅Br₂NO₄: V46.6%, H 5.13%, N 2.85%; actual:46.64%, H 5.16%, N 2.89%.

(iv) Preparation of4-[Bromo-(4-caboxy-phenyl)-methylene]-piperidine-1-carboxylic acidtert-butyl ester (Compound 51)

To a solution of compound 50 (5.4 g 11 mmol) in methanol (300 mL) at 40°C. was added 2.0 M NaOH (100 mL). The reaction was stirred for 3 hrs at40° C. The crude salt was isolated by filtration. The solid was driedovernight en vacuo. The dry salt was dissolved in 40% acetonitrile/waterand the pH was adjusted to 2 using concentrated HCl. The desired product(7) (3.8 g, 87%) was isolated as a white powder by filtration.

δ_(H) (400 MHz, CDCl₃) 1.45 (s, 9H), 2.22 (dd, J=5.5 Hz, 6.1 Hz, 2H),2.64 (dd, J=5.5 Hz, 6.1 Hz, 2H), 3.34 (dd, J=5.5 Hz, 6.1 Hz, 2H), 3.54(dd, J=5.5 Hz, 6.1 Hz, 2H), 7.35 (d, J=6.7 Hz, 2H), 8.08 (d, J=6.7 Hz,2H). δ_(c-13) (400 MHz, CDCl₃) 28.3, 31.5, 34.2, 44.0, 115.3, 128.7,129.4, 130.2, 137.7, 145.2, 154.6, 170.3.

Analysis calculated for: C₁₈H₂₂BrNO₄: C 54.56%, H 5.60%, N 3.53%;actual: C 54.66%, H 5.68%, N 3.59%.

(v) Preparation of4-[Bromo-(4-diethylcarbamoyl-phenyl)-methylene]-piperidine-1-carboxylicacid tert-butyl ester (Compound 52)

To a solution of compound 51 (1.0 g, 2.5 mmol) in dry dichloromethane(10 mL) at −20° C. was added iso-butylchloroformate (450 mg, 3.3 mmol).After 20 min at −20° C. diethylamine (4 mL) was added and the reactionwas allowed to warm to room temperature. After 1.5 hrs the solvent wasevaporated and the reaction mixture was partitioned between ethylacetate and water. The ethyl acetate was washed with water and brine anddried over MgSO₄ and removed by evaporation. The crude product waspurified by silica gel chromatography (0-60% ethyl acetate in heptanes)to give the product (compound 52) as white needles (800 mg, 73%).

δ_(H)(400 MHz, CDCl3) 1.13 (br, 3H), 1.22 (br, 3H), 1.44 (s, 9H), 2.22(t, J=5.5 Hz, 2H). 2.62 (t, J=5.5 Hz, 2H), 3.31 (t, J=5.5 Hz, 2H), 3.52(t, J=5.5 Hz, 2H), 7.27 (d, J=7.9 Hz. 2H), 7.33 (d, J=7.9 Hz, 2H).δ_(c-13) (400 MHz, CDCl₃) 12.71, 14.13, 28.3, 31.5, 34.2, 39.1, 43.2,79.7, 115.9, 126.3, 129.3, 136.8, 137.1, 140.6, 154.6, 170.5.

Analysis calculated for: C₂₂H₃₁BrN₂O₃: C 58.3%, H 6.92%, N6.21%; actual:C 58.62%, 6.89%, 6.21%.

EXAMPLE 27 Preparation ofN,N-Diethyl-4-[piperidin-4-ylidene(3-trifluoromethyl-phenyl)-methyl]-benzamide(Compound 54, Ar=3-Trifluoromethylphenyl)(general procedure)

The Suzuki coupling of compound 52 with a variety of boronic acids andthe subsequent deprotection were performed on a small scale in parallel.The reactions and liquid-liquid extractions were carried out in 25×150mm culture tubes. The protocol for a typical reaction is outlined below.

To a solution of compound 52 (25 mg, 57 μmol) and Tetrakis(triphenylphosphine) palladium(0) (5 mg, 4.3 μmol) in xylenes (degassed, 0.5 mL)was added 3-Trifluorophenyl boronic acid (28.5 mg, 150 μmol) in ethanol(degassed, 0.5 mL) followed by 150 μL of 2M Na₂CO₃ (aq) (300 μmol). Thereaction was allowed to procede at 80° C. for 1.5 hrs under Ar. Thereaction was diluted with water (1 mL) and diethyl ether (1 mL) andvortexed. The organic phase was isolated and evaporated to give a crudeproduct (compound 9, Ar=3-Trifluoromethylphenyl).

The Boc group was removed by treating the crude product with 1 mL ofTFA. After 30 minutes at room temperature the TFA was evaporated to givethe crude TFA salt. The salt was neutralized with 1 M NH₄OH(1.0M) andextracted into diethyl ether (2×1 mL). The ether phase was acidifiedwith 4.0 M HCl in dioxane (200 μL) and the HCl salt was extracted intowater (2×1 mL). The aqueous salt solution was washed with diethyl ether(2×1 mL) and lyophilized to yield the product (compound 54,Ar=3-Trifluoromethylphenyl) as a white powder (10 mg, 39%).

¹H NMR (CDCl₃) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.26 (t, J=5.6 Hz,2H), 2.31 (t, J=5.6 Hz, 2H), 2.88-2.91 (m, 4H), 3.27 (br, 2H), 3.52 (br,2H), 7.10-7.47 (m, *H).

Analysis calculated for: C₂₄H₂₈N₂OF₃Cl×1.80 H₂O: C, 59.39; H, 6.56; N,5.77; Actual: C, 59.39; H, 5.90; N, 5.77.

EXAMPLES 28-52

By following the same procedure as described for compound 54 of Example27 but substituting the respective boronic acids for3-trifluoromethylphenylboronic acid, the following compounds were alsoprepared.

EXAMPLE 28N,N-Diethyl-4-(3-nitrophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 55)

3-nitrophenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.21 (br, 3H), 2.27-2.34 (m, 4H),2.92 (t, J=6.0 Hz, 4H), 3.26 (br, 2H), 3.52 (br, 2H), 7.10 (d, J=8.4 Hz,2H), 7.31 (d, J=8.4 Hz, 2H), 7.40-7.50 (m, 2H), 7.95-8.08 (m, 2H)

EXAMPLE 29 N,N-Diethyl-4-(4-toluyl-piperidin-4-ylidene-methyl)-benzamide(Compound 56)

p-toluylboronic acid was used.

1H NMR (CDCl₃) (base) δ 1.10 (br, 3H), 1.19 (br, 3H), 2.29 (s, 3H),2.26-2.31 (m, 4H), 2.86-2.88 (m, 4H), 3.25 (br, 2H), 3.49 (br, 2H),6.95-7.28 (m, 8H)

EXAMPLE 30N,N-Diethyl-4-(4-formylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 57)

4-formylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.10 (br, 3H), 1.20 (br, 3H), 2.28-2.33 (m, 4H),2.89-2.92 (m, 4H), 3.25 (br, 2H), 3.50 (br, 2H), 7.08-7.79 (m, 8H), 9.95(s, 1H)

EXAMPLE 31N,N-Diethyl-4-(3-chloro-4-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 58)

3-chloro-4-fluorophenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.10 (br, 3H), 1.20 (br, 3H), 2.26-2.30 (m, 4H),2.86-2.91 (m, 4H), 3.25 (br, 2H), 3.50 (br, 2H), 6.93-7.30 (m, 7H)

EXAMPLE 32N,N-Diethyl-4-(4-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 59)

4-fluorophenylboronic acid was used.

1 HNMR (CDCl3) (base) δ 1.11 (br, 3H), 1.16 (br, 3H), 2.25 (s, 4H), 2.84(s, 4H), 3.20 (br, 2H), 3.47 (br, 2H), 6.92 (m, 2H), 7.01 (m, 4H), 7.23(d, J=8.8 Hz, 2H)

EXAMPLE 33N,N-Diethyl-4-(2-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 60)

2-fluorophenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.15 (br, 3H), 2.10 (t, J=5.2 Hz,2H), 2.27 (t, J=5.2 Hz, 2H), 2.83(m, 4H), 3.20 (br, 2H), 3.45 (br, 2H),6.94-7.03 (m, 3H), 7.10-7.23 (m, 5H)

EXAMPLE 34N,N-Diethyl-4-(2,4-dichlorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 61)

2,4-dichlorophenylboronic acid was used.

1H NMR (DMSO) (HCl salt) δ 1.07 (br, 6H), 2.24 (t, 2H), 2.50 (t, 2H),3.10 (t, 2H), 3.30 (t, 2H), 3.31 (br, 2H), 3.43 (br, 2H), 7.25 (d, J=8.4Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0Hz, 1H), 7.68 (s, 1H), 9.20 (br, 2H)

EXAMPLE 35N,N-Diethyl-4-(3,5-dichlorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 62)

3,5-dichlorophenylboronic acid was used.

1H NMR (DMSO) (HCl salt) δ 1.03 (br, 6H), 2.36-2.38 (m, 4H), 3.0-3.2 (m,4H), 3.2 (br, 2H), 3.38 (br, 2H), 7.19 (s, 1H), 7.21 (d, J=8.0 Hz, 2H),7.29 (d, J=8.0 Hz, 2H), 7.49 (s, 2H), 9.10 (br, 2H)

EXAMPLE 36N,N-Diethyl-4-(3-acetylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 63)

3-acetylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.26 (t, J=5.6 Hz,2H), 2.32 (t, J=5.6 Hz, 2H), 2.55 (s, 3H), 2.92-2.88 (m, 4H), 3.26 (br,2H), 3.51 (br, 2H), 7.11 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.29(d, J=7.2 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.79 (d, J=7.2Hz, 1H)

EXAMPLE 37N,N-Diethyl-4-(3,5-trifluoromethylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 64)

3,5-trifluoromethylphenylboronic acid was used.

1H NMR (DMSO) (HCl salt) δ 1.06 (br, 3H), 1.08 (br, 3H), 2.33 (br, 2H),2.41 (br, 2H), 3.12 (br, 6H), 3.38 (br, 2H), 7.24 (d, J=7.6 Hz, 2H),7.30 (d, J=7.6 Hz, 2H), 7.84 (s, 2H), 8.00 (s, 2H), 8.9 (br, 2H)

EXAMPLE 38N,N-Diethyl-4-(3-thiophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 65)

3-thiophenylboronic acid was used.

1 HNMR (DMSO) (HCl salt) δ 1.10 (br, 6H), 2.44 (t, 2H), 2.58 (t, 2H),3.10-3.15 (m, 4H), 3.21 (br, 2H), 3.44 (br, 2H), 6.86 (d, J=4.8 Hz, 1H),7.20 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.33 (s, 1H), 7.52 (d,J=4.8 Hz, 1H)

EXAMPLE 39N,N-Diethyl-4-(2-thiophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 66)

2-thiophenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.12 (br, 3H), 1.20 (br, 3H), 2.24 (t, J=5.2 Hz,2H), 2.50 (t, J=5.2 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H), 2.92 (t, J=5.6 Hz,2H), 3.27 (br, 2H), 3.51 (br, 2H), 6.75 (d, J=3.6 Hz, 1H), 6.93 (t,J=3.6 Hz, 1H), 7.16 (d, J=7.2 Hz, 2H), 7.21 (d, J=3.6 Hz, 1H), 7.30 (d,J=7.2 Hz, 2H)

EXAMPLE 40N,N-Diethyl-4-(4-methylthiophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 67)

4-methylthiophenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.32-2.75 (m, 4H),2.45 (s, 3H), 2.90-2.87 (m, 4H), 3.26 (br, 2H), 3.51 (br, 2H), 7.01 (d,J=6.0 Hz, 2H), 7,10 (d, J=6.0 Hz, 2H), 7.15 (d, J=6.8 Hz, 2H), 7.27 (d,J=6.8 Hz, 2H)

EXAMPLE 41N,N-Diethyl-4-(3-aminophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 68)

3-aminophenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.27-2.33 (m, 4H),2.86-2.90 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.57 (br, 2H), 3.68 (s,1H), 6.39 (s, 1H), 6.52 (dd, J=1.6 Hz, J=7.6 Hz, 2H), 7.06 (t, J=8.0 Hz,1H), 7.12 (d, J=6.4 Hz, 2H), 7.26 (d, J=6.4 Hz, 2H)

EXAMPLE 42N,N-Diethyl-4-(4-trifluoromethylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 69)

4-trifluoromethylphenylboronic acid was used.

1H NMR (DMSO) (HCl salt) δ 1.05 (br, 6H), 2.35 (t, 2H), 2.40 (t, 2H),3.09 (m, 6H), 3.35 (b,r, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz,2H), 7.35 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 8.71 (br, 2H)

EXAMPLE 43N,N-Diethyl-4-(4-methoxyphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 70)

4-methoxyphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.12 (br, 3H), 1.19 (br, 3H), 2.29 (m, 4H), 2.87(m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.77 (s, 3H), 6.80 (m, 2H), 7.00(m, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz)

EXAMPLE 44N,N-Diethyl-4-(3,4-dichlorophenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 71)

3,4-dichlorophenylboronic acid was used.

1 H NMR (CDCl3) (base) δ 1.12 (br, 3H), 1.20 (br, 3H), 2.28 (t, J=5.6Hz, 4H), 2.89 (m, 4H), 3.27 (br, 2H), 3.52 (br, 2H), 6.8-7.4 (m, 7H)

EXAMPLE 45N,N-Diethyl-4-(2-trifluoromethylphenyl-piperdine-4-ylidene-methyl)-benzamide(Compound 72)

2-trifluoromethylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.05 (br, 3H), 1.16 (br, 3H), 1.95 (m, 2H),2.35-2.41 (m, 2H), 2.7-2.9 (m, 4H), 3.20 (br, 2H), 3.48 (br, 2H),7.2-7.6 (m, 8H)

EXAMPLE 46 N,N-Diethyl-4-(3-toluyl-piperidin-4-ylidene-methyl)-benzamide(Compound 73)

m-tolylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.19 (br, 3H), 2.28 (s, 3H), 2.29(m, 4H), 2.89 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 6.8-7.3 (m, 8H)

EXAMPLE 47N,N-Diethyl-4-(2-methoxyphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 74)

2-methoxyphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.09 (br, 3H), 1.18 (br, 3H), 2.10 (q, J=4.8 Hz,2H), 2.31 (q, J=4.8 Hz, 2H), 2.8-2.9 (m, 4H), 3.25 (br, 2H), 3.50 (br,2H), 3.68 (s, 3H), 6.83-6.90 (m, 2H), 7.0 (d, 1H), 7.15-7.25 (m, 5H)

EXAMPLE 48N,N-Diethyl-4-(3-formylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 75)

3-formylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.15 (br, 3H), 1.20 (br, 3H), 2.26-2.34 (m, 4H),2.90-2.92 (m, 4H, 3.28 (br, 2H), 3.2 (br, 2H), 7.11-7.31 (m, 8H), 9.96(s, 1H)

EXAMPLE 49N,N-Diethyl-4-(2-naphtyl-piperidin-4-ylidene-methyl)-benzamide (Compound76)

2-naphtylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.35-2.39 (m, 4H),2.91-2.96 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 7.16-7.40 (m, 5H),7.42-7.44 (m, 2H), 7.57 (s, 1H), 7.72-7.79 (m, 2H)

EXAMPLE 50N,N-Diethyl-4-(2-formylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 77)

2-formylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.09 (br, 3H), 1.18 (br, 3H), 1.70-2.10 (m, 2H),2.40-2.49 (m, 2H), 2.76-2.84 (m, 2H), 2.85-2.97 (m, 2H), 3.23 (br, 2H),3.48 (br, 2H), 7.13-7.40 (m, 6H), 7.53-7.55 (m, 1H), 7.90 (d, J=7.6Hz,1H), 10.27 (s, 1H)

EXAMPLE 51N,N-Diethyl-4-(4-acetylphenyl-piperidin-4-ylidene-methyl)-benzamide(Compound 78)

4-acetylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.30-2.35 (m, 4H),2.56 (s, 3H), 2.92 (m, 4H), 3.27 (br, 2H), 3.52 (br, 2H), 7.10-7.30 (m,6H), 7.87 (d, J=7.2 Hz, 2H)

EXAMPLE 52N,N-Diethyl-4-(3-trifluoromethylphenyl-piperdin-4-ylidene-methyl)-benzamide(Compound 79)

3-trifluoromethylphenylboronic acid was used.

1H NMR (CDCl3) (base) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.26 (t, J=5.6 Hz,2H), 2.31 (t, J=5.6 Hz, 2H), 2.88-2.91 (m, 4H), 3.27 (br, 2H), 3.52 (br,2H), 7.10-7.47 (m, 8H)

EXAMPLE 53 Preparation ofN,N-Diethyl-4-([1-(2,6-Diamino-hexanoyl)-piperidin-4-ylidene]-phenyl-methyl)-benzamide(Compound 80).

L-Boc-Lysine(Cbz) (0.38 g, 1.0 mmol) was dissolved in drytetrahydrofuran (5 mL) under nitrogen at −15° C. N-Methylmorpholine(0.11 mL, 1.0 mmol) then isobutyl chloroformate (0.13 mL, 1 mmol) wasadded. After stirring 10 minutes,N,N-Diethyl-4-(phenyl-piperidin-4-ylidene-methyl)-benzamide (compound 6)(0.35 g, 1.0 mmol) was added in tetrahydrofuran (1 mL) and thetemperature was allowed to rise to 25° C. for 2 h. The reaction mixturewas evaporated onto silica gel. MPLC on silica gel (0 to 100% ethylacetate in heptane) gave 0.4 g.

The product (0.40 g, 0.56 mmol) was dissolved in methylene chloride (10mL) and treated with trifluoroacetic acid (3 mL) for 30 min, then thevolatiles were evaporated. The residue was dissolved in acetic acid (25mL) and subjected to hydrogenolysis 1.5 h with hydrogen (1 atm) overpalladium on carbon (10%, 0.10 g). The solvent was evaporated and theresidue purified by chromatography on a short reverse phase (RP-18)column, eluting with 0 to 30% acetonitrile in water. The free amine wasextracted with 5% potassium carbonate/methylene chloride to give 123 mgand then treated with two equivalents of hydrochloric acid inmethanol/water. Lyophilization gave the dihydrochloride salt.

¹H NMR: (free amine, CD₃OD): δ=1.0-1.7(m, 16H, amide-Me, piperidine-H,lysine-H), 2.3-2.7 and 3.0-4.5 (m, 11H, amide-H, piperidine-H,lysine-H),4.8 (s, 4H, 2 NH₂), 7.10-7.50 (m, 9H, Ar-H). C₂₉H₄₀N₄O₂×2.4H₂O×2 HCl, requires: C:58.76,H:7.96, N:9.43. Found C:58.70, H:7.51,N:9.33.

EXAMPLE 54 Preparation of4-[(4-Diethylcarbamoyl-phenyl)-phenyl-methylene]-piperidine-1-carboxylicacid phosphono-oxymethyl ester Compound 81)

N,N-Diethyl-4-(phenyl-piperidin-4-ylidene-methyl)-benzamide (compound 6)(0.62 g, 1.8 mmol) was dissolved in methylene chloride (10 mL) and1,8-bisdiaminonaphtalene (0.42 g, 2.0 mmol) was added. The solution wascooled to 0° C. and chloromethyl chloroformate (0.25 g, 2.0 mmol) addeddropwise in methylene chloride (1 mL). After 2 h at 25° C., a furtherportion of first 1,8-bisdiaminonaphtalene (0.21 g, 1.0 mmol), thenchloromethyl chloroformate (0.12 g,1.0 mmol) was added. After a total of4 hours, the solution was washed with 1 M HCl, brine and dried (MgSO₄)and evaporation gave 0.62 g. The residue was dissolved in toluene (25mL), silver dibenzylphosphate (0.81 g, 2.1 mmol) was added and themixture was heated 3 h at 80° C. The solution was filtered, then washedwith 5% potassium carbonate solution, brine, dried (K₂CO₃) andevaporated. MPLC on silica gel (0 to 100% ethyl acetate in heptane) gave0.66 g (0.96 mmol, 54%). The residue was dissolved in ethyl acetate (50mL) and subjected to hydrogenolysis (1 atm hydrogen) with palladium oncarbon (10%, 0.3 g) for 2 h. After filtration and evaporation of thesolvent, the product was treated with two equivalents of sodiumhydroxide in methanol/water. Lyophilization gave the disodium salt ofthe product as a white solid.

¹H NMR: (D₂O): δ=1.03, 1.20 (2 m, 6H, amide-Me), 2.34 (m, 4H,piperidine-H), 3.19-3.61 (m, 8H, amide—CH₂, piperidine-H), 5.44 (d, J=13Hz, 2H, OCH₂O), 7.18-7.36 (m, 9H, Ar—H).

Compounds 80 and 81 respectively, are suitable prodrugs of the compoundsof the general formula (I).

G) Synthetic Scheme For the Preparation of the Compounds of Examples55-57

The compounds of Examples 55, 56 and 57 were prepared by following theprocedure of Scheme 7 below.

(i) Preparation oftert-butyl-4-{bromo[4-(morpholinocarbonyl)phenyl]methylene}-1-piperidinecarboxylate(Compound 82)

To a solution of compound 51, prepared according to scheme 6, (0.25 g,0.625 mmole) and freshly distilled triethylamine (0.5 mL)indichloromethane (12 mL), was added oxalyl chloride (0.38 mL 2.0 M, 0.75mmole) dropwise at room temperature. The solution was stirred for 10minutes at room temperature and the solvent and excess reagents wereremoved in vacuo to give the acid chloride as a crude product which wasused in the next step without further purification.

Morpholine (56 mg, 0.65 mmole) was added to a solution of the acidchloride (0.65 mmole) and triethylamine (0.5 mL) in dichloromethane (5mL). The reaction was allowed to proceed for one hour at roomtemperature. The solvent was then removed in vacuo. The crude productwas partitioned between ethyl acetate (25 mL) and water (25 mL). Thewater was washed with ethyl acetate and the combined ethyl acetate waswashed with 2M NaOH (2×25 mL), (2M HCl (2×25 mL), brine (1×25 mL) anddried over magnesium sulfate. The solvent was removed in vacuo to givethe product (compound 82) (294 mg, 97% yield).

¹H nmr CDCl₃ (400 MHz) 1.44 (s, 9H), 2.21 (t, J=5.6 Hz, 2H), 2.62 (t,J=5.6 Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.69 (br,8H), 7.31 (d, J=6.4 Hz, 2H), 7.37 (d, J=6.4 Hz, 2H).

(ii) Preparation oftert-butyl-4-{bromo[4-(piperidinocarbonyl)phenyl]methylene}-1-piperidinecarboxylate(Compound 83)

Same procedure as described for the preparation of compound 82, butusing piperidine in place of morpholine.

¹H nmr CDCl₃ (400 MHz) 1.44 (s, 9H), 1.51 (br, 2H), 1.66 (br, 4H), 2.21(t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H), 3.31 (t, J=5.6 Hz, 2H),3.33(br, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.68 (br, 2H), 7.26 (d, J=8.4 Hz,2H), 7.35 (d, J=8.4 Hz, 2H)

(iii) Preparation oftert-butyl-4-{bromo[4-(tetrahydro-1H-1-pyrrolylcarbonyl)phenyl]methylene}-1-piperidinecarboxylate(Compound 84)

Same procedure as described for the preparation of compound 82, butusing pyrrolidine in place of morpholine.

¹H nmr CDCl₃ (400 MHz) 1.44 (s, 9H), 1.87 (q, J=6.8 Hz, 2H), 1.95 (q,J=6.8 Hz, 2H), 2.20 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H), 3.31 (t,J=5.6 Hz, 2H), 3.43 (t, J=6.8 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.63 (t,J=6.8 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H)

EXAMPLE 55 Preparation of4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-morpholin-4-yl-methanone(Compound 85)

To a solution of compound 82 (37 mg, 0.082 mmol) and tetrakis(triphenylphosphine) palladium(0) (5 mg, 0.0043 mmol) in xylenes (degassed, 0.5mL) was added 3-fluorophenyl boronic acid (25 mg, 0.18 mmol) in ethanol(degassed, 0.5 mL) followed by 150 μL 2M Na₂CO₃ (aq) (300 μmol). Thereaction was allowed to proceed at 80° C. for 2 hrs under argon. Thereaction was diluted with water (1 mL) and diethyl ether (1 mL) andvortexed. The organic phase was isolated and evaporated to give a crudeproduct which was used without further purification.

The Boc group was removed by treating the crude product with 1 mL ofTFA. After 30 minutes at room temperature the TFA was evaporated to givethe crude TFA salt. The salt was neutralized with 1 M NH₄OH (1.0 M) andextracted into diethyl ether (2×1 mL). The ether phase was acidifiedwith 4.0 M HCl in dioxane (200 μL) and the HCl salt was extracted intowater (2×1 mL). The aqueous salt solution was washed with diethyl ether(2×1 mL) and lyophilized to yield the product as a white powder.

¹H NMR CDCl₃ (400 MHz) δ 2.67 (m, 4H), 3.19 (m, 4H), 3.45 (br, 2H), 3.68(br, 6H), 6.75 (d, J=9.6 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.95 (m, 1H),7.11 (d, J=7.6 Hz, 2H), 7.25 (s, 1H), 7.35 (d, J=7.6 Hz, 2H).

EXAMPLE 56 Preparation of4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-piperidin-1-yl-methanone(Compound 86)

Same procedure as described for the preparation of compound 85, butusing compound 83 as starting material.

¹H NMR CDCl₃ (400 MHz) δ 1.51 (br, 2H), 1.65 (br, 4H), 2.60 (br, 4H),3.14 (br, 4H), 3.33 (br, 2H), 3.68 (br, 2H), 6.76 (d, J=8.0 Hz, 1H),6.86 (d, J=8.0 Hz, 1H), 6.93 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H),7.25 (s, 1H), 7.32 (d, J=8.4 Hz, 2H).

EXAMPLE 57 Preparation of4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-pyrolidin-1-yl-methanone(Compound 87)

Same procedure as for the preparation of compound 85, but using compound84 as starting material.

¹H NMR CDCl₃ (400 MHz) δ 1.84-1.89 (m, 2H), 1.90-1.98 (m, 2H), 2.60-2.63(m, 4H), 3.13-3.17 (m, 4H), 3.41 (t, J=6.8 Hz, 2H), 3.62 (t, J=6.8 Hz),6.73 (d, J=8.8 Hz, 1H), 6.86 (d, J=7.2 Hz, 1H), 6.93 (m, 1H), 7.10 (d,J=8.0 Hz, 2H), 7.25 (s, 1H), 7.45 (d, J=8.0 Hz, 2H).

H) Synthetic Scheme For the Preparation of the Compounds of Examples58-68

The compounds of Examples 58-68 were prepared by following the procedureof Scheme 8 (a)-(c) below.

(i) Preparation of4-[Bromo-(4-ethoxycarbonylamino-phenyl)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (Compound 88)

To a mixture of compound 51, prepared according to Scheme 6, (0.25 g,0.625 mmole) in toluene (5 mL), was added diphenylphosphorylazide (0.192g, 0.70 mmole) and triethylamine (0.1 mL, 0.7 mmole). After stirring themixture under argon at 95° C. for two hours an excess of anhydrousethanol (2 mL) and triethylamine (0.1 mL) were added and the solutionwas stirred at 95° C. for an additional 5 hours. After cooling to roomtemperature the reaction mixture was partitioned between water anddiethyl ether. The ether was washed with water, dried over magnesiumsulfate and removed in vacuo to give the product (compound 88) as a tanfoam (300 mg, 99% yield).

¹H NMR (400 MHz) (CDCl₃) 1.30 (t, J=7.2 Hz, 3H), 1.44 (s, 9H), 2.22 (t,J=6.0 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 3.31 (t, J=6.0 Hz, 2H), 3.51 (t,J=6.0 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H), 6.58 (s, 1H), 7.19 (d, J=8.4 Hz,2H), 7.33 (d, J=8.4 Hz, 2H).

(ii) Preparation of4-[(4-ethoxycarbonylaminophenyl)-(3-fluorophenyl)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (Compound 92)

The Suzuki coupling of the four vinyl bromides (compounds 88-91) with3-fluorophenyl boronic acid was performed in parallel. The reactions andliquid-liquid extractions were carried out in 25 mm×150 mm culturetubes. The protocol for a typical reaction is outlined below.

To a solution of compound 88 (0.30 g, 0.625 mmoles) andtetrakis(triphenyl phosphine), palladium(0) (50 mg) in toluene(degassed, 5 mL) was added 3-fluorophenyl boronic acid (0.182 g, 1.3mmoles) in ethanol (degassed, 5 mL) followed by 0.75 mL 2M Na₂CO₃ (aq)(1.5 mmoles). The reaction was allowed to proceed at 80° C. for 3 hrsunder argon. The reaction was diluted with water and diethyl ether andvortexed. The organic phase was isolated and evaporated to give a crudeproduct. The crude product was purified by silica gel chromatography(0-50% EtOAc in hexanes) to give the product (compound 92) as a whitepowder (0.166 g, 58% yield).

¹H NMR (400 MHz) (CDCl₃) δ 1.25 (t, J=7.2 Hz, 3H), 1.44 (s, 9H),2.27-2.33 (m, 4H), 3.41-3.44 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 6.52 (s,1H), 6.76 (d, J=10 Hz, 2H), 6.85-6.89 (m, 2H), 7.01 (d, J=8.8 Hz, 2H),7.19-7.23 (m, 1H), 7.28 (d, J=8.8 Hz, 2H)

EXAMPLE 58 Preparation of4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-carbamic Acid EthylEster (Compound 96)

The removal of the BOC protecting group was performed on a small scalein parallel in test tubes (13 mm×100 mm). A typical procedure isdescribed below.

The BOC group was removed by treating compound 92 (50 mg, 0.11 mmole)with HCl in dioxane (4.0 M, 2 mL). The mixture was stirred at roomtemperature for 30 minutes. The solvent and HCl were removed in vacuo toyield the product compound 96 as a white powder after lyophilization (40mg, 99% yield).

¹H NMR (400 MHz) (CDCl₃) δ 1.28 (t, J=7.2 Hz, 3H), 2.27-2.31 (m, 4H),2.85-2.91 (m, 4H), 4.19 (q, J=7.2 Hz, 2H), 6.50 (s, 1H), 6.76 d, J=10Hz, 1H), 6.85-6.89 (m, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.19-7.23 (m, 1H),7.28 (d, J=8.8 Hz, 2H).

EXAMPLE 59 Preparation of4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-methyl Carbamic AcidEthyl Ester (Compound 100)

The alkylation of the amide nitrogen was performed on a small scale inparallel in test tubes (13 mm×100 mm). A typical procedure is outlinebelow.

To a solution of compound 92 (50 mg, 0.11 mmoles) in dichloromethane(1.5 mL) was added methyl iodide (31 mg, 0.22 mmoles), aqueous sodiumhydroxide (1.0 mL, 2M) and tetrabutylammonium sulfate (44 mg, 0.13mmoles). The solution was refluxed for one hour. After cooling to roomtemperature the dichloromethane was separated and evaporated. Ether wasadded to the residue and the white tetrabutylammonium iodide was removedby filtration. The ether was removed in vacuo to give the crude productcompound 100 as a clear oil. The BOC group was removed by treatment withHCl in dioxane as described above to give the product as a white powderafter lyophilization (17 mg, 42% yield).

¹H NMR (400 MHz) (CDCl₃) δ 1.23 (t, J=7.2 Hz, 3H), 2.27-2.33 (m, 4H),2.85-2.91 (m, 4H), 3.26 (s, 3H), 4.15 (q, J=7.2 Hz, 2H), 6.78 (d, J=10Hz, 1H), 6.85-6.89 (m, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz,2H) 7.19-7.23 (m, 1H).

EXAMPLE 60 Preparation of4-[(1-benzylpiperidin-4-yl)-(3-fluorophenyl)-methyl]-phenyl-carbamicAcid Ethyl Ester (Compound 116)

The benzylation of compound 100 was performed on a small scale inparallel in test tubes (13 mm×100 mm). A typical procedure is outlinebelow.

The free base form of compound 100 was obtained by addition of ammoniumhydroxide (1M, 0.5 mL) to an aqueous solution of compound 100 (0.046mmoles) and extracted into ether. The ether was removed in vacuo to givean oil which was dissolved in dichloromethane and treated with benzylbromide (0.14 mL of 0.5 M in dichloromethane and triethylamine (0.05mL). The solution was stirred at room temperature for 5 hours. Thesolvent was removed in vacuo. The product was dissolved inwater/acetonitrile/HCl (2:1:0.5 M) and lyophilized to give the productcompound 108 as a white powder.

¹H NMR (400 MHz) (CDCl₃) δ 1.28 (t, J=7.2 Hz, 3H), 2.33-2.36 (m, 4H),2.38-2.46 (m, 4H), 3.51 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 6.50 (s, 1H),6.78 d, J=10 Hz, 1H), 6.85-6.89 (m, 2H), 7.05 (d, J=8.0 Hz, 2H),7.19-7.30 (m, 7H).

EXAMPLES 61-68

The following compounds were also made by following the synthesis routesdescribed in Schemes 8 (a)-(c).

TABLE 1 Characterization data [¹HNMR; 400 MHz Example Compound Chemicalstructure (CDCl₃)] Scheme 61 108

δ1.17(t, J=7.6Hz, 3H), 2.28-2.35(m, 4H), 2.40-2.45 (m, 4H), 3.21(s, 3H),3.50(s, 2H), 4.10(q, J=7.2Hz, 2H), 6.73(d, J=8.7Hz, 1H), 6.85 (m, 2H),7.01(d, J=8.8Hz, 2H), 7.2-7.3(m, 8H) 8 (c) 62 103

δ1.21(d, J=6.8Hz, 6H), 2.28(t, J=5.6Hz, 2H), 2.31 (t, J=5.6Hz, 2H),2.88(t, J=5.6Hz, 4H), 3.25(s, 3H), 4.93(quin, J=6.0Hz, 1H), 6.78(d, 1H),6.87(d, 2H), 7.04(d, 2H), 7.14(d, 2H), 7.15-7.29(m, 2H) 8 (b) 63 107

δ1.14(t, J=7.2Hz, 3H), 1.20(d, J=6.4Hz, 6H), 2.92 (t, J=5.2Hz, 2H),2.33(t, J=5.2Hz, 2H), 2.90(t, J=5.2 Hz, 4H), 3.66(q, J=7.6Hz, 2H),4.93(quin, J=6.0Hz, 1H), 6.79(d, 1H), 6.88(d, 2H), 7.02(d, 2H), 7.15(d,2H), 7.18-7.25(m, 2H) 8 (b) 64 102

δ2.27-2.33(m, 4H), 2.88- 2.90(m, 4H), 3.27(s, 3H), 3.70(s, 3H), 6.79(d,10Hz,1H), 6.88-6.90(m, 2H), 7.06 (d, J=8.4Hz, 2H), 7.13(d, J=8.4Hz, 2H),7.20-7.25(m, 1H) 8 (b) 65 106

δ1.13(t, J=6.8Hz, 3H), 2.27-2.33(m, 4H), 2.88- 2.90(m, 4H), 3.67(s, 3H),3.68(q, J=6.8Hz, 2H), 6.79 (d, 10Hz, 1H), 6.88-6.90 (m, 2H), 7.06(d,J=8.4Hz, 2H), 7.13(d, J=8.4Hz, 2H), 7.20-7.25(m, 1H) 8 (b) 66 104

δ1.13(t, J=6.8Hz, 3H), 1.21(t, J=7.2Hz, 3H), 2.30-2.36(m, 4H), 2.91-2.93(m, 4H), 3.67(q, J=6.8 Hz, 2H), 4.13(q, J=6.8Hz, 2H), 6.79(d, 10Hz,1H), 6.88-6.90(m, 2H), 7.06(d, J=8.4Hz, 2H), 7.13(d, J=8.4Hz, 2H),7.20-7.25 (m, 1H) 8 (b) 67  99

δ1.26(d, J=6.0Hz, 6H), 2.27-2.32(m, 4H, 2.87- 2.89(m, 4H), 4.95-5.02(m,1H), 6.56(s, 1H), 6.79(d, 10Hz, 1H), 6.88-6.90(m, 2H), 7.01(d, J =8.4Hz,2H), 7.20-7.25(m, 1H), 7.27(d, J=8.4Hz, 2H) 8 (b) 68  98

δ2.27-2.31(m, 4H), 2.86- 2.89(m, 4H), 3.75(s, 3H), 6.64(s, 1H),6.76-6.80(m, 1H), 6.85-7.00(m, 2H), 7.02(d, J=8.8Hz, 2H), 7.18-7.22(m,1H), 7.28(d, J=8.8Hz, 2H) 8 (b)

The best mode of performing the invention known at present, is to usethe compounds 6, 7, 9, 10, 12, 26. 27, 34, 39, 44, 58, 59, 62, 69, 71,104, 106, and 109.

Pharmaceutical Compositions

The novel compounds according to the present invention may beadministered orally, intramuscularly, subcutaneously, topically,intranasally, intraperitoneally, intrathoracially, intravenously,epidurally, intrathecally, intracerebroventricularly and by injectioninto the joints.

A preferred route of administration is orally, intravenously orintramuscularly.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level at the most appropriate for a particularpatient.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Pharmaceutically acceptable salts are acetate, benzenesulfonate,benzoate, bicarbonate. bitartrate, bromide, calcium acetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glucaptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate mesylate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate(embonate), pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, triethiodide, benzathine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine, procaine, aluminium,calcium, lithium, magnesium, potassium, sodium, and zinc.

Preferred pharmaceutically acceptable salts are the hydrochlorides andcitrates.

The term composition is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid from compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical compositions is in unit dosage form. Insuch form, the composition is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powdersin vials or ampoules. The unit dosage form can also be a capsule,cachet, or tablet itself, or it can be the appropriate number of any ofthese packaged forms.

BIOLOGICAL EVALUATION A) IN VITRO MODEL

Cell Culture

Human 293S cells expressing cloned human μ, δ, and κ receptors andneomycin resistance were grown in suspension at 37° C. and 5% CO₂ inshaker flasks containing calcium-free DMEM 10% FBS, 5% BCS, 0.1%Pluronic F-68, and 600 μg/ml geneticin.

Membrane Preparation

Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0,2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 Mstock in ethanol), incubated on ice for 15 min, then homogenized with apolytron for 30 sec. The suspension was spun at 1000 g (max) for 10 minat 4° C. The supernatant was saved on ice and the pellets resuspendedand spun as before. The supernatants from both spins were combined andspun at 46,000 g(max) for 30 min. The pellets were resuspended in coldTris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pelletswere resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dryice/ethanol and stored at −70° C. until use. The protein concentrationswere determined by a modified Lowry assay with SDS.

Binding Assays

Membranes were thawed at 37° C., cooled on ice, passed 3 times through a25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mMMgCl₂, 1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4° C.after filtration through a 0.22 m filter, and to which had been freshlyadded 5 μg/ml aprotinin, 10 μM bestatin, 10 μM diprotin A, no DTT).Aliquots of 100 μl (for μg protein, see Table 1) were added to iced12×75 mm polypropylene tubes containing 100 μl of the appropriateradioligand (see Table 1) and 100 μl of test peptides at variousconcentrations. Total (TB) and nonspecific (NS) binding were determinedin the absence and presence of 10 μM naloxone respectively. The tubeswere vortexed and incubated at 25° C. for 60-75 min, after which timethe contents are rapidly vacuum-filtered and washed with about 12mil/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl₂) through GF/Bfilters (Whatman) presoaked for at least 2 h in 0.1% polyethyleneimine.The radioactivity (dpm) retained on the filters was measured with a betacounter after soaking the filters for at least 12 h in minivialscontaining 6-7 ml scintillation fluid. If the assay is set up in96-place deep well plates, the filtration is over 96-place PEI-soakedunifilters, which were washed with 3×1 ml wash buffer, and dried in anoven at 55° C. for 2 h. The filter plates were counted in a TopCount(Packard) after adding 50 μl MS-20 scintillation fluid/well.

Data Analysis

The specific binding (SB) was calculated as TB-NS, and the SB in thepresence of various test peptides was expressed as percentage of controlSB. Values of IC₅₀ and Hill coefficient (n_(H)) for ligands indisplacing specifically bound radioligand were calculated from logitplots or curve fitting programs such as Ligand, GraphPad Prism,SigmaPlot, or ReceptorFit. Values of K_(i) were calculated from theCheng-Prussoff equation. Mean±S.E.M. values of IC₅₀, K_(i) and n_(H)were reported for ligands tested in at least three displacement curves.

Receptor Saturation Experiments

Radioligand K_(δ) values were determined by performing the bindingassays on cell membranes with the appropriate radioligands atconcentrations ranging from 0.2 to 5 times the estimated K_(δ) (up to 10times if amounts of radioligand required are feasable). The specificradioligand binding was expressed as pmole/mg membrane protein. Valuesof K_(δ) and B_(max) from individual experiments were obtained fromnonlinear fits of specifically bound (B) vs. nM free (F) radioligandfrom individual according to a one-site model.

B) BIOLOGICAL MODEL (IN VIVO MODEL) FREUND'S COMPLETE ADJUVANT (FCA),AND SCIATIC NERVE CUFF INDUCED MECHANO-ALLODYNIA IN RAT

Animals

Male Sprague-Dawley rats (Charles River, St-Constant, Canada) weighing175-200 g at the time of surgery were used. They were housed in groupsof three in rooms thermostatically maintained at 20° C. with a 12:12 hrlight/dark cycle, and with free access to food and water. After arrival,the animals were allowed to acclimatize for at least 2 days beforesurgery. The experiments were approved by the appropriate MedicalEthical Committee for animal studies.

EXPERIMENTAL PROCEDURE FREUND'S COMPLETE ADJUVANT

The rats were first anesthetized in a Halothane chamber after which 10μl of FCA was injected s.c. into the dorsal region of the left foot,between the second and third external digits. The animals were thenallowed to recover from anesthesia under observation in their home cage.

SCIATIC NERVE CUFF

The animals were prepared according to the method described by Mosconiand Kruger (1996). Rats were anesthetized with a mixture ofKetamine/Xylazine i.p. (2 ml/kg) and placed on their right side and anincision made over, and along the axis of, the lateral aspect of theleft femur. The muscles of the upper quadriceps were teased apart toreveal the sciatic nerve on which a plastic cuff (PE-60 tubing, 2 mmlong) was placed around. The wound was then closed in two layers with3-0 vicryl and silk sutures.

DETERMINATION OF MECHANO-ALLODYNIA USING VON FREY TESTING

Testing was performed between 08:00 and 16:00 h using the methoddescribed by Chaplan et al. (1994). Rats were placed in Plexiglas cageson top of a wire mesh bottom which allowed access to the paw, and wereleft to habituate for 10-15 min. The area tested was the mid-plantarleft hind paw, avoiding the less sensitive foot pads. The paw wastouched with a series of 8 Von Frey hairs with logarithmicallyincremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and15.14 grams; Stoelting, Ill., USA). The von Frey hair was applied fromunderneath the mesh floor perpendicular to the plantar surface withsufficient force to cause a slight buckling against the paw, and heldfor approximately 6-8 seconds. A positive response was noted if the pawwas sharply withdrawn. Flinching immediately upon removal of the hairwas also considered a positive response. Ambulation was considered anambiguous response, and in such cases the stimulus was repeated.

TESTING PROTOCOL

The animals were tested on postoperative day 1 for the FCA-treated groupand on post-operative day 7 for the Sciatic Nerve Cuff group. The 50%withdrawal threshold was determined using the up-down method of Dixon(1980). Testing was started with the 2.04 g hair, in the middle of theseries. Stimuli were always presented in a consecutive way, whetherascending or descending. In the absence of a paw withdrawal response tothe initially selected hair, a stronger stimulus was presented; in theevent of paw withdrawal, the next weaker stimulus was chosen. Optimalthreshold calculation by this method requires 6 responses in theimmediate vicinity of the 50% threshold, and counting of these 6responses began when the first change in response occurred, e.g. thethreshold was first crossed. In cases where thresholds fell outside therange of stimuli, values of 15.14 (normal sensitivity) or 0.41(maximally allodynic) were respectively assigned. The resulting patternof positive and negative responses was tabulated using the convention,X=no withdrawal; O=withdrawal, and the 50% withdrawal threshold wasinterpolated using the formula:

50% g threshold=10^((Xf+kδ))/10,000

where Xf=value of the last von Frey hair used (log units); k=tabularvalue (from Chaplan et al. (1994)) for the pattern of positive/negativeresponses; and δ=mean difference between stimuli (log units). Hereδ=0.224.

Von Frey thresholds were converted to percent of maximum possible effect(% MPE), according to Chaplan et al. 1994. The following equation wasused to compute % MPE:${\% \quad {MPE}} = {\frac{{{Drug}\quad {treated}\quad {threshold}\quad (g)} - {{allodynia}\quad {threshold}\quad (g)}}{{{Control}{\quad \quad}{threshold}\quad (g)} - {{allodynia}\quad {threshold}\quad (g)}} \times 100}$

ADMINISTRATION OF TEST SUBSTANCE

Rats were injected (subcutaneously, intraperitoneally, or orally) with atest substance prior to von Frey testing, the time betweenadministration of test compound and the von Frey test varied dependingupon the nature of the test compound.

Definitions

The following abbreviations have the indicated meanings:

Ac=acetyl

Ar=aryl

t-BOC=tertiary-butoxycarbonyl

t-Bu=tertiary-butyl

Et=ethyl

iPr=isopropyl

Me=methyl

Ph=phenyl

Pr=propyl

r.t.=room temperature

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TMEDA=N,N,N′,N′-tetramethylethylenediamine

What is claimed is:
 1. A compound of the general formula (I)

wherein: R¹ is selected from hydrogen, a branched or straight C₁-C₆alkyl, C₁-C₆ alkenyl, C₃-C₈ cycloalkyl, C₄-C₈(alkyl-cycloalkyl) whereinalkyl is C₁-C₂ alkyl and cycloalkyl is C₃-C₆ cycloalkyl; C₆-C₁₀ aryl; orheteroaryl having from 5 to 10 atoms selected from any of C, S, N and O;wherein the aryl and heteroaryl may optionally and independently besubstituted by 1 or 2 substituents independently selected from any ofhydrogen, CH₃, —(CH₂)_(p)CF₃, halogen, —CONR⁵R⁴, —COOR⁵, —COR⁵,—(CH₂)_(p)NR⁵R⁴, —(CH₂)_(p)CH₃(CH₂)_(p)SOR⁵R⁴, —(CH₂)_(p)SO₂R⁵, and—(CH₂)_(p)SO₂NR⁵, wherein R⁴ and R⁵ are each and independently asdefined for R¹ above and p is 0, 1 or 2; (C₁-C₂ alkyl)-(C₆-C₁₀ aryl); or(C₁-C₂ alkyl)heteroaryl, the heteroaryl moieties having from 5 to 10atoms selected from any of C, S, N and O, and where the aryl orheteroaryl may optionally and independently be substituted by 1 or 2substituents independently selected from any of hydrogen, CH₃,—(CH₂)_(q)CF₃, halogen, —CONR⁵R⁴, —COOR⁵, —COR⁵, —(CH₂)_(q)NR⁵R⁴,—(CH₂)_(q)CH₃(CH₂)_(q)SOR⁵R⁴, —(CH₂)_(q)SO₂R⁵, —(CH₂)_(q)SO₂NR⁵ and—(CH₂)_(p)OR⁵, wherein R⁴ and R⁵ are each and independently as definedfor R¹ above and q is 0, 1 or 2; and

wherein R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ is each andindependently hydrogen, C₁-C₆ alkyl or C₁-C₆ alkenyl; R² and R³ are eachand independently hydrogen or C₁-C₆ alkyl; A is selected from

wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each andindependently as defined for R¹ above, and wherein the phenyl ring ofeach A substituent may be optionally and independently substituted atany position of the phenyl ring by 1 or 2 substituents Z¹ and Z² whichare each and independently selected from hydrogen, CH₃, —(CH₂)_(q)CF₃,halogen, CONR⁶R⁷, —COOR6, —COR⁶, —(CH₂)_(r)NR⁶R⁷,—(CH₂)_(r)CH₃(CH₂)_(r)SOR⁶, —(CH₂)_(r)SO₂R⁶ and —(CH₂)_(r)SO₂NR⁶R⁷wherein R⁶ and R⁷ are each and independently as defined for R¹ above andr is 0, 1, or 2; Q is C₅-C₆ hydroaryl or heterohydroaromatic having 5 or6 atoms selected from any one of C, S, N and O; C₅-C₆ cykloalkyl, orheterocycloalkyl having 5 or 6 atoms selected from any one of C, N, Oand S; and where each Q may optionally be substituted by a substituentZ¹ and Z² as defined above; B is a substituted or unsubstitutedaromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moietyhaving from 5 to 10 atoms selected from any of C, S, N and O, optionallyand independently substituted by 1 or 2 substituents independentlyselected from hydrogen, CH₃, —(CH₂)_(t)CF_(3,) halogen,—(CH₂)_(t)CONR⁵R⁴, —(CH₂)_(t)NR⁵R⁴, —(CH₂)_(t)COR⁵, —(CH₂)_(t)COOR⁵,—OR⁵, —(CH₂)_(t)SOR⁵, —(CH₂)_(t)SO₂R⁵, and —(CH₂)_(t)SO₂NR⁵R⁴, whereinR⁴and R⁵ are each and independently as defined for R¹ above, and t is 0,1, 2 or 3; R⁴ and R⁵ are each and independently as defined for R¹ above;or a pharmaceutically acceptable salt, isomer, hydrate, isoform orprodrug thereof.
 2. A compound of the formula (I) according to claim 1,wherein A is selected from

wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is each andindependently as defined for R¹ above, and wherein the phenyl ring ofeach A substituent may be optionally and independently substituted atany position of the phenyl ring by 1 or 2 substituents Z¹ and Z² whichare each and independently selected from hydrogen, CH₃, —(CH₂)_(q)CF₃,halogen, —CONR⁶R⁷, —COOR⁶, —COR⁶, —(CH₂)_(r)NR⁶R⁷,—(CH₂)_(r)CH₃(CH₂)_(r)SOR⁶, —(CH₂)_(r)SO₂R⁶ and —(CH₂)_(r)SO₂NR⁶R⁷wherein R⁶ and R⁷ is each and independently as defined for R¹ above, andr is 0, 1, or 2; Q is selected from morpholine, piperidine andpyrrolidine; R¹, R⁴, and R⁵ is each and independently selected fromhydrogen, a branched or straight C₁-C₄ alkyl, C₃-C₅ cycloalkyl, C₄-C₈(alkyl-cycloalkyl) wherein alkyl is C₁-C₂ alkyl and cycloalkyl is C₃-C₆cycloalkyl; C₆-C₁₀ aryl; and heteroaryl having from 5 to 6 atomsselected from any of C, S, N and O; and where the aryl or heteroaryl mayoptionally and independently be substituted by 1 or 2 substituentsindependently selected from any of hydrogen, CH₃, —(CH₂)_(p)CF₃,halogen, —CONR⁵R⁴, —COOR⁵, —COR⁵, —(CH₂)_(p)NR⁵R⁴,—(CH₂)_(p)CH₃(CH₂)_(p)SOR⁵R⁴, —(CH₂)_(p)SO₂R⁵, and —(CH₂)_(p)SO₂NR⁵,wherein R⁴ and R⁵ is each and independently as defined for R¹ above andp is 0, 1 or 2; B is selected from phenyl, naphthyl, indolyl,benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl,quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl,tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, andindazolinyl, each optionally and independently substituted by 1 or 2substituents independently selected from hydrogen, CH₃, CF₃, halogen,—(CH₂)_(q)CONR⁵R⁴, —(CH₂)_(q)NR⁵R⁴, —(CH₂)_(q)COR⁵, —(CH₂)_(q)CO₂R₅, and—OR⁵, wherein q is 0 or 1, and wherein R⁴ and R⁵ are as defined above;R² and R³ is each and independently hydrogen or methyl.
 3. A compound ofthe formula (I) according to claim 1, which compound is any of


4. A compound according to any of the preceding claims, in form of itshydrochloride, sulfate, tartrate or citrate salt.
 5. An isotopicallylabelled compound of claim
 1. 6. A pharmaceutical composition in unitdose form comprising a compound according to claim 1 as an activeingredient, said compound being present in an amount such that one ormore unit doses are effective in treating pain or spinal injury,together with a pharmacologically and pharmaceutically acceptablecarrier.
 7. A process for the preparation of a compound of the formula(I) according to claim 1, comprising a) reacting a ketone of the formula(l)

wherein R¹, R² and R³ are as defined in claim 1, and X is a leavinggroup, with an organometallic reagent of the formula (j) or (k)

wherein A and B are as defined in claim 1, and M is a metal group; andwherein the reaction is optionally performed in the presence of asolvent, giving a compound of the formula (h)

wherein A, B, R¹, R² and R³ are as defined in claim 1, and wherein R1also may be tert-butoxycarbonyl; b) dehydrating the compound of theformula (h) to give a compound of the formula (I) of claim
 1. 8. Acompound of the formula

wherein A, B, R² and R³ are defined as follows: R² and R³ are each andindependently hydrogen or C₁-C₆ alkyl; A is selected from

wherein the phenyl ring of each A substituent may be optionally andindependently substituted at any position of the phenyl ring by 1 or 2substituents Z¹ and Z² which are each and independently selected fromhydrogen, CH₃, —(CH₂)_(q)CF₃, halogen, CONR⁶R⁷, —COOR⁶, —COR⁶,—(CH₂)_(r)NR⁶R⁷, —(CH₂)_(r)CH₃(CH₂)_(r)SOR⁶, —(CH₂)_(r)SO₂R⁶ and—(CH₂)_(r)SO₂NR⁶R⁷ wherein R⁶ and R⁷ are each and independently asdefined for R¹ above and r is 0, 1, or 2; and wherein R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each and independently: hydrogen, abranched or straight C₁-C₆ alkyl, C₁-C₆ alkenyl, C₃-C₈ cycloalkyl,C₄-C₈(alkyl-cycloalkyl) wherein alkyl is C₁-C₂ alkyl and cycloalkyl isC₃-C₆ cycloalkyl; C₆-C₁₀ aryl; or heteroaryl having from 5 to 10 atomsselected from any of C, S, N and O; wherein the aryl and heteroaryl mayoptional and independently be substituted by 1 to 2 substituentsindependently selected from any of hydrogen, Ch₃, —(CH₂)_(p)CF₃,halogen, —CONR⁵R⁴, —COOR⁵, —COR⁵, —(CH₂)_(p)NR⁵R⁴,—(CH₂)_(p)CH₃(CH₂)_(p)SOR⁵R⁴, —(CH₂)_(p)SO₂R⁵, and —(CH₂)_(p)SO₂NR⁵,wherein R⁴ and R⁵ are each and independently as defined for R¹ above andp is 0, 1 or 2; (C₁-C₂ alkyl)-(C₆-C₁₀ aryl); or (C₁-C₂ alkyl)heteroaryl, the heteroaryl moieties having from 5 to 10 atoms selectedfrom any of C, S, N and O, and where the aryl or heteroaryl mayoptionally and independently be substituted by 1 to 2 substituentsindependently selected from any of hydrogen, CH₃, —(CH₂)_(q)CF₃,—CONR⁵R⁴, —COOR⁵, —COR⁵, —(CH₂)_(q)NR⁵R⁴, —(CH₂)_(q)CH₃(CH₂)_(q)SOR⁵R⁴,—(CH₂)_(q)SO₂R⁵, —(CH₂)_(q)SO₂NR⁵ and —(CH₂)_(p)OR⁵, wherein R⁴ and R⁵are each and independenlty as defined for R¹ above and q is 0, 1 or 2;and

wherein R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴ are each and independentlyhydrogen, C₁-C₆ alkyl or C₁-C₆ alkenyl; Q is a C₅-C₆ hydroaryl orheterohydroaromatic having 5 or 6 atoms selected from any one of C, S, Nand O; C₅-C₆ cycloalkyl, or heterocycloalkyl having 5 or 6 atomsselected from any one of one of C, N, O and S; and where each Q mayoptionally by substituted by a substitutent by a substituent Z¹ and Z²as defined above; B is a substituted or unsubstituted aromatic,heteroaromatic, hydroaromatic or heterohydroaromatic moiety having from5 to 10 atoms selected from any of C, S, N and O, optionally andindependently substituted by 1 to 2 substituents independently selectedfrom hydrogen, CH₃, —(CH₂)_(t)CF₃, halogen, —(CH₂)_(t)CONR⁵R⁴,—(CH₂)_(t)NR⁵R⁴, —(CH₂)_(t)COR⁵, —(CH₂)_(t)COOR⁵, —OR⁵, —(CH₂)_(t)SOR⁵,—(CH₂)_(t)SO₂R⁵, and —(CH₂)_(t)SO₂NR⁵R⁴, wherein R⁴ and R⁵ are each andindependently as defined for R¹ above, and t is 0, 1, 2 or 3; R⁴ and R⁵are each and independently as defined for R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶and R¹⁷ above.
 9. A method of treating a patient for pain,comprising administering an analgesically effective amount of a compoundaccording to claim 1 to said patient.
 10. A method of treating a patientfor a spinal injury, comprising administrating a delta opioid receptorantagonistic effective amount of a compound according to claim 1 to saidpatient.